Pyridazine derivatives and drugs containing the same as the active ingredient

ABSTRACT

This invention relates to pyridazine derivatives represented by the formula (1):                    
     wherein R 1  represents a lower alkoxyl group, a lower alkylthio group or a halogen atom; R 2  represents H, a lower alkoxyl group, a lower alkylthio group or a halogen atom; R 3  represents a lower alkyl or lower alkenyl group, which may be substituted by one or more OHs, CNs, lower cycloalkyl groups, (substituted) aromatic groups or (substituted) carbamoyl groups; R 4  represents COOH, a lower alkoxycarbonyl group, a (substituted) carbamoyl group, a (substituted) amino group, or a (substituted) ureido group; and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond, or salts thereof; and also to medicines containing them as effective ingredients. These compounds have excellent inhibitory activity against interleukin-1β production, and are useful as preventives and therapeutics for immune system diseases, inflammatory diseases, ischemic diseases and the like.

TECHNICAL FIELD

This invention relates to novel pyridazine derivatives, which haveexcellent inhibitory activity against interleukin-1β production and areuseful for the prevention and treatment of immune system diseases,inflammatory diseases, ischemic diseases and the like, and also tomedicines containing them as effective ingredients.

BACKGROUND ART

In many diseases, for example, rheumatism, arthritis, osteoporosis,inflammatory colitis, immune deficiency syndrome, ichorrhemia,hepatitis, nephritis, ischemic diseases, insulin-dependent diabetesmellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease,leukemia and the like, stimulation of interleukin-1β production, aninflammatory cytokine, is observed. This interleukin-1β serves to inducesynthesis of an enzyme which is considered to take part in inflammationlike collagenase and PLA2 and, when intra-articularly injected toanimals, causes multiarticular destruction highly resembling rheumatoidarthritis. On the other hand, interleukin-1β is controlled in activityby interleukin-1β receptor, soluble interleukin-1 receptor andinterleukin-1 receptor antagonist.

From research conducted making use of recombinants of thesebioactivity-inhibiting substances, anti-interleukin-1β antibodies andanti-receptor antibodies against various disease models, interleukin-1βhas been found to play an important role in the body, leading to anincreasing potential of substances having interleukin-1β inhibitoryactivity as therapeutics for such diseases.

For example, immunosuppressors and steroids which are used for thetreatment of rheumatism out of such many diseases have been reported toinhibit the production of interleukin-1β. Even among medicamentscurrently under development, KE298, a benzoylpropionic acid derivative[The Japanese Society of Inflammation (11th), 1990], for example, hasbeen reported to have inhibitory activity against interleukin-1βproduction although it is an immunoregulator. Inhibitory activityagainst interleukin-1β production is also observed on a group ofcompounds which are called “COX-2 selective inhibitors”,for example,nimesulide as a phenoxysulfonanilide derivative (DE 2333643), T-614 as aphenoxybenzopyran derivative (U.S. Pat. No. 4,954,518), and tenidap(hydroxyindole derivative) as a dual inhibitor (COX-1/5-LO).

For all of these compounds, however, interleukin-1β productioninhibitory activity is not their primary action so that their inhibitoryactivity against interleukin-1β production is lower than their primaryaction.

In recent years, increasingly active research is under way for thesynthesis of compounds with a focus placed on inhibitory activityagainst interleukin-1β production. Inhibitors synthesized in suchresearch can be classified into a group of compounds which inhibit thetransfer process of an inflammatory signal to a cell nucleus and anothergroup of compounds which inhibit an enzyme ICE that functions in theprocessing of a precursor of interleukin-1β Known examples of compoundspresumed to have the former action include SB203580 [Japanese LanguageLaid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J.Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A(Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur.J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO97/05878), while known examples of compounds presumed to have the latteraction include VE-13,045 which is a peptide compound (Cytokine, 8(5),377-386, 1996).

None of these compounds can however exhibit sufficient inhibitoryactivity against interleukin-1β production.

On the other hand, it is known that a variety of 5,6-diphenylpyridazinederivatives have analgesic and anti-inflammatory action (EUR. J. MED.CHEM., 14, 53-60, 1979) and also that 3,4,5,6-substituted pyridazinederivatives have inhibitory activity against interleukin-1β convertingenzymes [Japanese Patent Application Laid-Open (Kokai) No. HEI 7-69894].Absolutely nothing has however been known with respect to inhibitoryactivity of 2,4,6-substituted pyridazin-3-one derivatives againstinterleukin-1β production.

Accordingly, an object of the present invention is to provide a compoundhaving excellent inhibitory activity against interleukin-1β productionand also a medicine containing it as an effective ingredient.

DISCLOSURE OF THE INVENTION

Under such circumstances, the present inventors have proceeded with anextensive investigation. As a result, it has been found that pyridazinederivatives represented by the below-described formula (1) haveexcellent inhibitory activity against interleukin-1β production and areuseful for the prevention and treatment of immune system diseases,inflammatory diseases, ischemic diseases and the like, leading to thecompletion of the present invention.

Namely, the present invention provides a pyridazine derivativerepresented by the following formula (1):

wherein R¹ represents a lower alkoxyl group, a lower alkylthio group ora halogen atom; R² represents a hydrogen atom, a lower alkoxyl group, alower alkylthio group or a halogen atom; R³ represents a linear orbranched lower alkyl or lower alkenyl group, which may have one or moresubstituents each independently selected from a hydroxyl group, ahalogen atom, a cyano group, a lower cycloalkyl group, a substituted orunsubstituted aromatic group or a substituted or unsubstituted carbamoylgroup; R⁴ represents a carboxyl group, a lower alkoxycarbonyl group, asubstituted or unsubstituted thiocarbamoyl group, a substituted orunsubstituted amino group, or a substituted or unsubstituted ureidogroup; and the dashed line indicates that the carbon-carbon bond betweenthe 4-position and the 5-position is a single bond or a double bond; ora salt thereof.

Further, the present invention also provides a medicine comprising thepyridazine derivative (1) or the salt thereof as an effectiveingredient.

Furthermore, the present invention also provides a pharmaceuticalcomposition comprising the pyridazine derivative (1) or the salt thereofand a pharmaceutically acceptable carrier.

Moreover, the present invention also provides use of the pyridazinederivative (1) or the salt thereof as a medicine.

In addition, the present invention also provides a method for treating adisease caused by stimulation of interleukin-1β production, whichcomprises administering the pyridazine derivative (1) or the saltthereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The pyridazine derivative according to the present invention isrepresented by the formula (1). In the formula, illustrative of thelower alkoxyl groups represented by R¹ and R² can be those having 1 to 6carbon atoms, for example, methoxy, ethoxy and propoxy. Illustrative ofthe lower alkylthio groups can be those having 1 to 6 carbon atoms, forexample, methylthio, ethylthio and propylthio. Illustrative of thehalogen atoms can be fluorine, chlorine, bromine and iodine.

Preferred as R¹ is a fluorine atom, a lower alkoxyl group or a loweralkylthio group, while preferred as R² is a hydrogen atom, a halogenatom or a lower alkoxyl group.

Examples of the lower alkyl group out of those represented by R³ caninclude linear or branched lower alkyl groups having 1 to 6 carbonatoms, for example, methyl, ethyl, n-propyl, isopropyl and n-butyl.Examples of the lower alkenyl group can include linear or branched loweralkenyl groups having 2 to 9 carbon atoms, more preferably 2 to 6 carbonatoms and 1 to 3 double bonds, for example, ethenyl, propenyl andbutenyl.

These lower alkyl groups and lower alkenyl groups may have one or moresubstituents each independently selected from a hydroxyl group, ahalogen atom, a cyano group, a lower cycloalkyl group, a substituted orunsubstituted aromatic group, or a substituted or unsubstitutedcarbamoyl group.

Examples of the lower cycloalkyl group can include those having 3 to 8carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.

Examples of the aromatic group can include aromatic hydrocarbon groupsand aromatic heterocyclic groups, for example, phenyl, naphthyl andpyridyl, with phenyl and pyridyl being particularly preferred. Thesearomatic groups may each contain 1 to 3 substituents. Examples of suchsubstituents can include halogens, nitro, amino, andaromatic-group-substituted carbonylamino groups. Illustrative ofaromatic group(s) substituted on the carbonylamino group can be phenyland pyridyl.

Illustrative of substituent(s) which the carbamoyl group may have can belower alkyl groups, lower alkyl groups each of which may be substitutedby one or more hydroxyl groups or aromatic groups, and aromatic groupseach of which may be substituted by one or more lower alkylthio groups.

Further, examples of the halogen atoms, aromatic groups, lower alkylgroups and lower alkylthio groups can be similar ones as thoseexemplified above (including those exemplified as R¹ and R²).

R³ may preferably be an alkyl group having 1 to 6 carbon atoms or alower alkenyl group having 2 to 9 carbon atoms, which may have one ormore substituents each independently selected from a hydroxyl group, ahalogen atom, a cyano group or a lower cycloalkyl group; a phenyl orpyridyl group which may have 1 to 3 substituents each independentlyselected from a halogen atom, a nitro group, an amino group or anaromatic-group-substituted carbonylamino group; or a carbamoyl groupwhich may have one or more substituents each independently selected froma lower alkyl groups, hydroxy lower alkyl group, anaromatic-group-substituted lower alkyl group or a lower alkylthiophenylgroup.

Examples of the lower alkoxycarbonyl group out of those represented byR⁴ can include carbonyl groups each of which has an alkoxyl group having1 to 6 carbon atoms, for example, methoxycarbonyl, ethoxycarbonyl andbutoxycarbonyl.

Examples of the substituent(s) in the substituted carbamoyl orthiocarbamoyl group can include lower alkyl groups, which may have oneor more substituents such as aromatic groups, and aromatic groups.

Examples of the substituent(s) in the substituted amino group caninclude lower alkoxycarbonyl groups each of which may have one or moresubstituents such as aromatic groups; acyl groups; lower alkyl groupseach of which may have one or more substituents such as aromatic groups;and lower alkylsulfonyl groups. Illustrative of the acyl groups can bethose having 1-5 carbon atoms, for example, formyl, acetyl, propionyland butyryl.

Examples of the substituent(s) in the substituted ureido group caninclude lower alkyl groups.

Incidentally, specific examples of the individual groups, such as thelower alkyl group, aromatic group and lower alkoxyl group, representedby R⁴ can be similar to those exemplified above with respect to R¹, R²and R³.

R⁴ may preferably be a carboxyl group; a lower alkoxycarbonyl group; acarbamoyl or thiocarbamoyl group which may have one or moresubstitutents each independently selected from a lower alkyl group, anaromatic group or an aromatic-group-substituted lower alkyl group; anamino group which may have one or more substituents each independentlyselected from a lower alkoxycarbonyl group, anaromatic-group-substituted lower alkoxycarbonyl group, an acyl group, alower alkyl group, an aromatic-group-substituted lower alkyl group or alower alkylsulfonyl group; or a ureido group which may have one or morelower alkyl groups as substituents.

Further, the dashed line in the formula (1), namely, the carbon-carbonbond between the 4-position and the 5-position may preferably be adouble bond.

Preferred examples of the pyridazine derivative (1) can include thoserepresented by the same formula in which R¹ represents a fluorine atom,a lower alkoxyl group or a lower alkylthio group; R² represents ahydrogen atom, a halogen atom or a lower alkoxyl group; R³ represents alinear or branched lower alkyl group having 1 to 6 carbon atoms or alinear or branched lower alkenyl group having 2 to 9 carbon atoms, whichmay have one or more substitutents each independently selected from ahydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group;a phenyl or pyridyl group which may have 1 to 3 substituents eachindependently selected from a halogen atom, a nitro group, an aminogroup or an aromatic-group-substituted carbonylamino group; or acarbamoyl group which may be have one or more substituents eachindependently selected from a lower alkyl group, a hydroxy lower alkylgroup, an aromatic-group-substituted lower alkyl group or a loweralkylthiophenyl group; and R⁴ represents a carboxyl group; a loweralkoxycarbonyl group; a carbamoyl or thiocarbamoyl group which may haveone or more substituents each independently selected from a lower alkylgroup, an aromatic group or an aromatic-group-substituted lower alkylgroup; an amino group which may be have one or more substitutents eachindependently selected from a lower alkoxycarbonyl group, anaromatic-group-substituted lower alkoxycarbonyl group, an acyl group, alower alkyl groups, an aromatic-group-substituted lower alkyl group or alower alkylsulfonyl group; or a ureido group which may have one or morelower alkyl groups as substituents.

Specific preferred examples can include2-isobutyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-(cyclopropylmethyl)-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-(cyclopropylmethyl)-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-(cyclopropylmethyl)-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one,or2-(4-chlorocinnamyl)-4-formylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one.

No particular limitation is imposed on the salt of the pyridazine (1),said salt also pertaining to the present invention, insofar as it is apharmacologically acceptable salt. Illustrative can be acid additionsalts of mineral acids, such as the hydrochloride, hydrobromide,hydroiodide, sulfate, nitrate and phosphate; and acid addition salts oforganic acids, such as the benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, oxalate, maleate, fumarate,tartrate and citrate.

Further, the compounds according to the present invention may exist inthe form of solvates represented by hydrates and also in the form ofketo-enol tautomers. Such solvates and isomers should also beencompassed by the present invention.

The pyridazine derivatives (1) according to the present invention can beprepared, for example, by the following processes.

wherein R⁵ represents a lower alkyl group, R⁶ and R⁷ each independentlyrepresent a hydrogen atom, a substituted or unsubstituted lower alkylgroup or an aromatic group, R⁸ represents a substituted or unsubstitutedlower alkyl group, R⁹ represents a substituted or unsubstituted loweralkyl group, R¹⁰ represents an acyl group, a lower alkylsulfonyl, or asubstituted or unsubstituted carbamoyl group, X represents an oxygenatom or a sulfur atom, and R¹, R² and R³ have the same meanings asdefined above.

A description will be made specifically about respective preparationprocesses of compounds (1a), (1b), (1c), (1d), (1e), (1f), (1g), (1h)and (1i) among the pyridazine derivatives (1).

(1) Preparation of compounds (1a) of the formula (1) in which R⁴ is alower alkoxycarbonyl group and a double bond is formed between the4-position and the 5-position:

Each compound (1a) can be obtained by reacting a compound (3), which hasbeen obtained by esterifying a compound (2) by a method known per se inthe art, with a compound (5), which is represented by R³-Y wherein R³has the same meaning as defined above and Y represents a halogen atom oran OH group already converted into a reactive ester group, in thepresence of a base in a solvent.

The compound (2) employed here can be prepared, for example, by theprocess disclosed in Japanese Patent Application Laid-Open (Kokai) No.HEI 7-69891.

As the reactive ester group of the hydroxyl group, a tosyloxy group, amesyloxy group, a benzenesulfonyloxy group or the like is preferred. Acompound which contains such a group can be obtained by reactingpara-toluenesulfonyl chloride, methanesulfonyl chloride, methanesulfonicanhydride, benzenesulfonyl chloride or the like with a hydroxylderivative in the presence of a base such as pyridine, triethylamine orcollidine. The reaction is brought to completion at −15 to 50° C. in 1to 50 hours, preferably at −5 to 30° C. in 1 to 10 hours. As a solvent,pyridine, tetrahydrofuran, diethyl ether, ethyl acetate, methylenechloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or thelike can be used.

Examples of the base for use in the reaction between the compound (3)and the compound (5) can include inorganic bases such as potassiumcarbonate and sodium carbonate and organic bases such as pyridine,triethylamine, and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU). Usableexamples of the solvent can include N,N-dimethylformamide,dimethylsulfoxide, acetone, methyl ethyl ketone, chloroform, methylenechloride, toluene, and benzene. The reaction is brought to completion at20 to 150° C. in 1 to 20 hours, preferably at 50 to 130° C. Among thecompounds (1a), one containing an aminophenylalkyl group as R³ can beobtained by reducing the nitro group of a compound (1a) in which R³ is anitrophenylalkyl group. Further, N-acylation of the aminophenylalkylgroup makes it possible to obtain a compound in which R³ is anN-acylaminophenylalkyl group.

(2) Preparation of compounds (1b) of the formula (1) in which R⁴ is asubstituted or unsubstituted carbamoyl group and a double bond is formedbetween the 4-position and the 5-position:

Each compound (1b) can be obtained by reacting in a solvent the compound(3) with an amine, which is represented by R⁶R⁷NH₂ in which R⁶ and R⁷have the same meanings as defined above, to give the compound (4),followed by reacting it as a raw material in a similar manner as in thereaction between the compound (3) and the compound (5). In the reactionbetween the compound (3) and the amine, it is preferable to use theamine in an amount of from 1 to 30 equivalents, especially from 2 to 15equivalents relative to the compound (3). Usable examples of the solventcan include methanol, ethanol, isopropanol, tetrahydrofuran, andN,N-dimethylformamide. The reaction is brought to completion at −10 to200° C. in 0.5 to 24 hours, preferably at 20 to 150° C. in 0.5 to 3hours.

On the other hand, the reaction between the compound (4) and thecompound (5) is brought to completion at 20 to 150° C. in 1 to 20 hours,preferably at 50 to 130° C. in 2 to 10 hours.

Among the compounds (1b), one containing an arylalkylcarbamoylalkylgroup or a hydroxyalkylcarbamoylalkyl group as R³ can be obtained byreacting an arylalkylamine or a hydroxyalkylamine with a compound (1b)in which R³ is an alkoxycarbonylalkyl group.

Each of the compounds (1b) can also be obtained by reacting the compound(1a) as a raw material in a similar manner as in the reaction conductedupon conversion of the compound (3) into the compound (4).

(3) Preparation of compounds (1i) of the formula (1) in which R⁴ is asubstituted or unsubstituted carbamoyl group and a single bond is formedbetween the 4-position and the 5-position:

Each compound (1i) can be obtained by subjecting the compound (1b) tocatalytic reduction in a manner known per se in the art. The reactioncan be conducted by effecting hydrogenation at room temperature or underheating in the presence of palladium on charcoal, Raney nickel or thelike as a catalyst in a solvent such as methanol, ethanol or ethylacetate.

(4) Preparation of compounds (1c) of the formula (1) in which R⁴ is acarboxyl group and a double bond is formed between the 4-position andthe 5-position:

Each compound (1c) can be obtained by hydrolyzing the compound (1a)under acidic or basic conditions in a solvent by a method known per sein the art.

Examples of an acid can include hydrochloric acid, sulfuric acid andtrifluoroacetic acid, while examples of a base can include sodiumhydroxide, potassium hydroxide and barium hydroxide. Usable examples ofthe solvent can include mixed solvents of water with methanol, ethanol,isopropanol, tetrahydrofuran, N,N-dimethylformamide and the like. Thereaction is brought to completion at 0 to 150° C. in 10 minutes to 5hours, preferably at 20 to 100° C. in 30 minutes to 2 hours.

(5) Preparation of compounds (1d) of the formula (1) in which R⁴ is asubstituted or unsubstituted alkoxycarbonylamino group and a double bondis formed between the 4-position and the 5-position:

Each compound (1d) can be obtained by reacting a compound (1c) with analcohol, which is represented by R⁸OH in which R⁸ has the same meaningas defined above, and diphenylphosphoryl azide (DPPA) in the presence ofa base in a solventless manner or in a solvent.

Examples of the solvent can include benzene and toluene. Usable examplesof the base can include triethylamine. The reaction is brought tocompletion at 50 to 150° C. in 0.5 to 24 hours, preferably at 80 to 120°C. in 1 to 8 hours.

(6) Preparation of compounds (1e) of the formula (1) in which R⁴ is anamino group substituted by a substituted or unsubstituted lower alkylgroup and a lower alkoxycarbonyl group and a double bond is formedbetween the 4-position and the 5-position:

Each compound (1e) can be obtained by reacting a compound (1d) with acompound, which is represented by R⁹-Y wherein R⁹ and Y have the samemeanings as defined above, in the presence of a base in a solvent. Thereaction can be conducted in a similar manner as the above-describedreaction between the compound (3) and the compound (5).

(7) Preparation of compounds (1f) of the formula (1) in which R⁴ is anamino group substituted by a substituted or unsubstituted lower alkylgroup and a double bond is formed between the 4-position and the5-position:

Each compound (1f) can be obtained by hydrolyzing a compound (1e) underacidic or basic conditions in a solvent by a method known per se in theart

Examples of an acid can include hydrochloric acid and sulfuric acid,while examples of a base can include sodium hydroxide, potassiumhydroxide and barium hydroxide. Usable examples of the solvent caninclude mixed solvents of water with methanol, ethanol, isopropanol,tetrahydrofuran, N,N-dimethylformamide and the like. The reaction isbrought to completion at 0 to 180° C. in 10 minutes to 24 hours,preferably at 20 to 120° C. in 0.5 to 8 hours.

(8) Preparation of compounds (1g) of the formula (1) in which R⁴ is anamino group and a double bond is formed between the 4-position and the5-position:

Each compound (1g) can be obtained by hydrolyzing the compound (1d)under acidic or basic conditions in a solvent by a method known per sein the art.

Examples of an acid can include hydrochloric acid and sulfuric acid,while examples of a base can include sodium hydroxide, potassiumhydroxide and barium hydroxide. Usable examples of the solvent caninclude mixed solvents of water with methanol, ethanol, isopropanol,tetrahydrofuran, N,N-dimethylformamide and the like. The reaction isbrought to completion at 0 to 180° C. in 10 minutes to 24 hours,preferably at 2 to 120° C. in 0.5 to 8 hours.

(9) Preperation of compounds (1h) of the formula (1) in which R⁴ is anacylamino group, a lower alkylsulfonylamino group or a substituted orunsubstituted ureido group and a double bond is formed between the4-position and the 5-position:

(i) Each compound (1h) in which R⁴ is an acylamino group can be obtainedby reacting a compound (1g) with a compound, which is represented byR¹¹COX or (R¹¹CO)₂O wherein R¹¹ represents a lower alkyl group, an arylgroup or a lower aralkyl group and X represents a halogen atom, in thepresence of a base in a solvent.

Examples of the solvent can include pyridine, tetrahydrofuran, dioxane,ethyl acetate, chloroform, toluene and benzene. It is also possible touse a mixed solvent of water and ethyl acetate, chloroform, toluene,benzene or the like. Usable examples of the base can include organicbases such as pyridine, triethylamine and DBU and inorganic bases suchas sodium hydroxide, potassium hydroxide, potassium carbonate and sodiumcarbonate. The reaction is brought to completion at −15 to 100° C. in 1to 50 hours, preferably at −5 to 50° C. in 2 to 25 hours.

(ii) Each compound (1h) in which R⁴ is a lower alkylsulfonylamino groupcan be obtained by reacting, in a solvent and in the presence of a base,the compound (1g) with 2 equivalents or more of a compound, which isrepresented by R¹¹SO₂X or (R¹¹SO₂)₂O wherein R¹¹ and X have the samemeanings as defined above in a similar manner as in the process (i), togive a di(lower alkylsulfonyl)amino derivative, followed by hydrolyzingit under basic conditions in a solvent.

Examples of the solvent for use in the hydrolysis can include mixedsolvents of water and methanol, ethanol, isopropanol, tetrahydrofuran,N,N-dimethylformamide and the like. Usable examples of the base caninclude organic bases such as pyridine and inorganic bases such assodium hydroxide, potassium hydroxide, potassium carbonate and sodiumcarbonate. The reaction is brought to completion at −15 to 100° C. in 10minutes to 10 hours, preferably at 0 to 80° C. in 0.5 to 5 hours.

(iii) Each compound (1h) in which R⁴ is a substituted or unsubstitutedureido group can be obtained by reacting the compound (1g) with acompound, which is represented by R¹¹NCO wherein R¹¹ has the samemeaning as defined above, in a solvent.

Usable examples of the solvent can include toluene and benzene. Thereaction is brought to completion at 20 to 150° C. in 0.5 to 30 hours,preferably at 50 to 120° C. in 1 to 8 hours.

(10) Compounds (1b) or compounds (1i) of the formula (1) in each ofwhich R⁴ is a substituted or unsubstituted thiocarbamoyl group can eachbe obtained by converting X of the compound (1b) or the compound (1i),in which X is an oxygen atom, into a sulfur atom. For example, X in thecompound (1b) in which X is an oxygen atom can be converted into asulfur atom by reacting the compound (1b) with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) ina solvent. It is preferred to use Lawesson's reagent in 0.5 to 3equivalents, notably 1 to 1.5 equivalents relative to the compound (1b).The reaction is brought to completion at 30 to 150° C. in 1 to 20 hours,preferably at 50 to 100° C. in 5 to 15 hours. Usable examples of thesolvent can include toluene and xylene.

(11) Preparation of compounds (1i) of the formula (1) in which R⁴ is asubstituted or unsubstituted carbamoyl group or thiocarbamoyl group anda single bond is formed between the 4-position and the 5-position:

Each compound (1i) can be prepared by hydrogenating the compound (1b),in which R⁴ is a substituted or unsubstituted carbamoyl group orthiocarbamoyl group, in a solvent in the presence of palladium oncharcoal or the like as a catalyst. Usable examples of the solvent caninclude methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate,and N,N-dimethylformamide. The reaction is brought to completion at 15to 200° C. in 1 to 50 hours, preferably at 50 to 120° C. in 2 to 20hours.

The intermediates and target compounds obtained in the above-describedindividual reactions can be separated and purified by purificationmethods commonly employed in organic synthesis chemistry, for example,by subjecting them to filtration, extraction, washing, drying,concentration, recrystallization, various chromatographic treatment, andthe like. The intermediates may be provided for the next reactionswithout purifying them specifically. Further, they may also be obtainedas solvates of solvents such as reaction solvents or recrystallizationsolvents, especially as hydrates.

The pyridazine derivatives (1) and their salts according to the presentinvention, which are available as described above, have excellentinhibitory activity against interleukin-1β production, and are usefulfor the prevention and treatment of diseases caused by stimulation ofinterleukin-1β production, for example, immune system diseases,inflammatory diseases, ischemic diseases, osteoporisis, ichorrhemia andthe like, especially as medicines such as preventives and therapeuticsfor rheumatism, immune deficiency syndrome, arthritis, inflammatorycolitis, ischemic heart diseases, ischemic encephalopathy, ischemicnephritis, ischemic hepatitis, insulin-dependent diabetes mellitus,arterial sclerosis, Parkinson's disease, Alzheimer's disease, leukemiaand the like or as interleukin-1β production inhibitors.

Medicines according to the present invention contain the pyridazinederivatives (1) or their salts as effective ingredients. Theiradministration routes can include, for example, oral administration bytablets, capsules, granules, powders, syrups or the like and parenteraladministration by intravenous injections, intramuscular injections,suppositories, inhalants, transdermal preparations, eye drops, nasaldrops or the like. Upon formulation of pharmaceutical compositions ofthese various unit dosage forms, the effective ingredients can be usedsingly or in combination with pharmaceutically acceptable carriers, forexample, excipients, binders, extenders, disintegrators, surfactants,lubricants, dispersants, buffers, preservatives, corrigents, perfumes,coating agents, vehicles, diluents or the like, as desired.

The dosage of each medicine according to the present invention variesdepending on the age, body weight, conditions, administration form,administration frequency and the like. In general, however, it ispreferred to orally or parenterally administer to an adult the effectiveingredient in an amount of about 0.01 to 1,000 mg, preferably 0.1 to 100mg per day at once or in several portions.

EXAMPLES

The present invention will next be described in further detail by thefollowing Examples. It should however be borne in mind that the presentinvention is not limited to these Examples.

Example 1 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one

Potassium carbonate (346 mg, 2.50 mmol) and methyl iodide (284 mg, 2.00mmol) were added to a solution of4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (260 mg, 1.00mmol) in N,N-dimethylformamide (5 ml), followed by stirring at 60° C.for 2 hours. Inorganic matter was filtered off, the solvent wasdistilled off under reduced pressure, and the residue was then separatedand purified by chromatography on a silica gel column [silica gel: 20 g,ethyl acetate/hexane (2/1)]. Crystallization was conducted fromchloroform-hexane, whereby the title compound (233 mg, 85.0%) wasobtained as yellow needles.

Melting point: 109.2-109.5° C.; ¹H-NMR (CDCl₃) δ: 3.87(3H,s),3.92(3H,s), 3.97(3H,s), 6.99(2H,d,J=8.9 Hz), 7.75(2H,d,J=8.9 Hz),8.23(1H,s). IR (KBr) cm⁻¹: 1743,1713,1660,1607,1518,1278,1250,1141,1120,1101,839. Mass (m/z): 274 (M⁺).

Example 2 Preparation of2-Ethyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyliodide as starting materials, the procedures of Example 1 were repeatedlikewise, whereby the title compound was obtained in a yield of 79.4%.

Pale yellow needles (chloroform-hexane); Melting point: 76.5-77.6° C.;¹H-NMR (CDCl₃) δ: 1.46(3H,t,J=7.2 Hz), 3.87(3H,s), 3.98(3H,s),4.35(2H,q,J=7.2 Hz), 6.99(2H,d,J=8.9 Hz), 7.76(2H,d,J=8.9 Hz),8.22(1H,s). IR (KBr) cm⁻¹: 1749,1721,1712,1661,1599,1519,1272. Mass(m/z): 288 (M⁺).

Example 3 Preparation of2-Cyanomethyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-2-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one andbromoacetonitrile as starting materials, the procedures of Example 1were repeated likewise, whereby the title compound was obtained in ayield of 77.4%.

Yellow prisms (chloroform-hexane); Melting point: 128.0-129.8° C.(dec.); ¹H-NMR (CDCl₃) δ: 3.88(3H,s), 4.00(3H,s), 5.15(2H,s),7.01(2H,d,J=9.0 Hz), 7.78(2H,d,J=9.0 Hz), 8.31(1H,s). IR (KBr) cm⁻¹:1721,1669,1608,1520,1313,1276,1251. Mass (m/z): 299 (M⁺).

Example 4 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-n-propyl-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one andbromopropane as starting materials, the procedures of Example 1 wererepeated likewise, whereby the title compound was obtained in a yield of78.3%.

Pale yellow needles (chloroform-hexane); Melting point: 104.8-105.8° C.;¹H-NMR (CDCl₃) δ: 1.00(3H,t,J=7.4 Hz), 1.84-1.99(2H,m), 3.87(3H,s),3.98(3H,s), 4.26(2H,t,J=7.4 Hz), 6.99(2H,d,J=8.9 Hz), 7.75(2H,d,J=8.9Hz), 8.21(1H,s). IR (KBr) cm⁻¹: 1718,1668,1609,1519,1316,1277,1253,1187,1021,838,797. Mass (m/z): 302 (M⁺).

Example 5 Preparation of2-(2-Cyanoethyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and3-chloropropionitrile as starting materials, the procedures of Example 1were repeated likewise, whereby the title compound was obtained in ayield of 78.9%.

Yellow prisms (chloroform-hexane); Melting point: 140.6-143.1° C.;¹H-NMR (CDCl₃) δ: 2.99(2H,t,J=6.7 Hz), 3.87(3H,s), 3.99(3H,s),4.56(2H,t,J=6.7 Hz), 7.00(2H,d,J=9.0 Hz), 7.77(2H,d,J=9.0 Hz),8.28(1H,s). IR (KBr) cm⁻¹: 2246,1717,1664,1520,1275,1250. Mass (m/z):313 (M⁺).

Example 6 Preparation of2-(2-Chloroethyl)-4-ethyoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and1-bromo-2-chloroethane as starting materials, the procedures of Example1 were repeated likewise, whereby the title compound was obtained in ayield of 88.8%.

Yellow needles (chloroform-hexane); Melting point: 97.2-97.7° C.; ¹H-NMR(CDCl₃) δ: 1.43(3H,t,J=7.3 Hz), 3.87(3H,s), 3.97(2H,t,J=6.4 Hz),4.45(2H,q,J=7.3 Hz), 4.61(2H,t,J=6.4 Hz), 7.00(2H,d,J=8.9 Hz),7.75(2H,d,J=8.9 Hz), 8.21(1H,s). IR (KBr) cm⁻¹:1707,1673,1605,1523,1389,1321,1275,1261, 1184,1130,1034,842. Mass (m/z):338 (M⁺), 336 (M⁺).

Example 7 Preparation of4-Ethoxycarbonyl-6-(4-methoxyphenyl)-2-vinyl-2H-pyridazin-3-one and4-ethoxycarbonyl-2-(2-hydroxyethyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Potassium carbonate (115 mg, 0.83 mmol) was added to a solution of2-(2-chloroethyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(140 mg, 0.15 mmol) in N,N-dimethylformamide (1 ml), followed bystirring at 80° C. for 2 hours. Inorganic matter was filtered off, thesolvent was distilled off under reduced pressure, and the residue wasthen subjected to chromatography on a silica gel column (silica gel: 5g). From ethyl acetate/hexane (½) eluate fractions, the title compound[4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-vinyl-2H-pyridazin-3-one; 34 mg,27.2%) was obtained as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.87(3H,s), 4.44(2H,q,J=7.1 Hz),5.10(1H,d,J=8.5 Hz), 5.95(1H,d,J=8.5 Hz), 7.00(2H,d,J=8.8 Hz),7.80(2H,d,J=8.8 Hz), 7.87(1H,dd,J=8.5,15.6 Hz), 8.18(1H,s).

Subsequently, from chloroform/methanol (20/1) eluate fractions, thetitle compound[4-ethoxycarbonyl-2-(2-hydroxyethyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one(93 mg, 70.4%) was obtained as yellow crystals.

Yellow needles (chloroform-hexane); Melting point: 104.6-105.4° C.;¹H-NMR (CDCl₃) δ: 1.41(3H,t,J=7.3 Hz), 2.75(1H,br), 3.86(3H,s),4.11(2H,t,J=5.1 Hz), 4.44(2H,q,J=7.3 Hz), 4.50(2H,t,J=5.1 Hz),6.99(2H,d,J=8.6 Hz), 7.73(2H,d,J=8.6 Hz), 8.19(1H,s). IR (KBr) cm⁻¹:3426,1717,1706,1655,1596,1520,1389,1316, 1266,1027,831,795. Mass (m/z):318 (M⁺).

Example 8 Preparation of6-(3-Chloro-4-fluorophenyl)-2-cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-one

Using 6-(3-chloro-4-fluorophenyl)-4-ethoxycarbonyl-2H-pyridazin-3-oneand cinnamyl bromide as starting materials, the procedures of Example 1were repeated likewise, whereby the title compound was obtained in ayield of 59.3%.

Pale yellow oil; ¹H-NMR (CDCl₃) δ: 1.43(3H,t,J=7.3 Hz), 4.45(2H,q,J=7.3Hz), 5.04(2H,dd,J=1.0,6.6 Hz), 6.44(1H,td,J=6.6,15.8 Hz),6.77(1H,d,J=15.8 Hz), 7.21-7.41(7H,m), 7.90(1H,dd,J=2.3,6.9 Hz),8.17(1H,s). IR (film) cm⁻¹: 1749,1668,1605,1504,1264,1148,1021,968,924,753,693.

Example 9 Preparation of4-Ethoxycarbonyl-2-isopropyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and2-bromopropane as starting materials, the procedures of Example 1 wererepeated likewise, whereby the title compound was obtained in a yield of86.7%.

Pale yellow needles (chloroform-hexane); Melting point: 140.6-141.1° C.;¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 1.44(6H,d,J=6.6 Hz), 3.87(3H,s),4.44(2H,q,J=7.1 Hz), 5.39-5.54(1H,m), 6.99(2H,d,J=9.0 Hz),7.77(2H,d,J=9.0 Hz), 8.14(1H,s). IR (KBr) cm⁻¹:1713,1664,1601,1518,1390,1323,1271,1177, 1132,1030,829. Mass (m/z): 316(M⁺).

Example 10 Preparation of4-Ethoxycarbonyl-2-isobutyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Potassium carbonate (605 mg, 4.38 mmol) and 1-bromo-2-methylpropane (360mg, 2.63 mmol) were added to a solution of4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (600 mg, 2.19mmol) in N,N-dimethylformamide (6 m), followed by stirring at 80° C. for30 minutes. After inorganic matter was filtered off, the solvent wasdistilled off under reduced pressure. The residue was separated andpurified by chromatography on a silica gel column [silica gel: 15 g,hexane/ethyl acetate (1/1)], whereby the title compound (705 mg, 97.5%)was obtained.

Pale yellow needles (chloroform-hexane); Melting point: 83.0-83.3° C.;¹H-NMR (CDCl₃) δ: 0.99(6H,d,J=6.8 Hz), 1.42(3H,t,J=7.1 Hz),2.29-2.45(1H,m), 3.87(3H,s), 4.11(2H,d,J=7.3 Hz), 4.44(2H,q,J=7.1 Hz),6.99(2H,d,J=8.9 Hz), 7.75(2H,d,J=8.9 Hz), 8.17(1H,s). IR (KBr) cm⁻¹:1717,1709,1665,1599,1518,1388,1333,1271, 1177,1159,1113,1019,829. Mass(m/z): 330 (M⁺).

Example 11 Preparation of6-(3,4-Dimethoxyphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and1-bromo-2-methylpropane as starting materials, the procedures of Example1 were repeated likewise, whereby the title compound was obtained in ayield of 86.6%.

Yellow needles (chloroform-hexane); Melting point: 104.2-105.5° C.;¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.8 Hz), 2.29-2.45(1H,m), 3.94(3H,s),3.98(3H,s), 4.02(3H,s), 4.13(2H,d,J=7.3 Hz), 6.94(2H,d,J=8.6 Hz),7.33(1H,dd,J=2.2,8.6 Hz), 7.38(1H,d,J=2.2 Hz), 8.23(1H,s). IR (Kbr)cm⁻¹: 1710,1665,1522,1429,1423,1297,1248,1228, 1177,1112,1026. Mass(m/z): 346 (M⁺).

Example 12 Preparation of6-(3-Fluoro-4-methoxyphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3 -one

Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneand 1-bromo-2-methylpropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 69.9%.

Yellow needles (chloroform-hexane); Melting point: 119.3-121.3° C;¹H-NMR (CDCl₃) δ: 0.99(6H,d,J=6.6 Hz), 2.37-2.44(1H,m), 3.95(3H,s),3.98(3H,s), 4.11(2H,d,J=7.3 Hz), 6.99-7.07(1H,m), 7.47-7.53(1H,m),7.57-7.64(1H,m), 8.23(1H,s). IR (KBr) cm⁻¹:1746,1660,1522,1434,1290,1195,1178,1136, 1099,1013.

Example 13 Preparation of6-(3-Chloro-4-methoxyphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneand 1-bromo-2-methylpropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 79.5%.

Yellow needles (chloroform-hexane); Melting point: 108.2-109.4° C.;¹H-NMR (CDCl₃) δ: 0.99(6H,d,J=6.6 Hz), 2.29-2.45(1H,m), 3.97(3H,s),3.98(3H,s), 4.12(2H,d,J=7.3 Hz), 7.01(1H,d,J=8.8 Hz),7.67(1H,dd,J=2.2,8.8 Hz), 7.86(1H,d,J=2.2 Hz), 8.19(1H,s). IR (KBr)cm⁻¹: 1713,1663,1603,1510,1293. Mass (m/Z): 352 (M⁺), 350 (M⁺).

Example 14 Preparation of2-Isobutyl-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and1-bromo-2-methylpropane as starting materials, the procedures of Example1 were repeated likewise, whereby the title compound was obtained in ayield of 77.3%.

Yellow needles (chloroform-hexane); Melting point: 90.4-91.4° C.; ¹H-NMR(CDCl₃) δ: 0.99(6H,d,J=6.6 Hz), 2.29-2.42(1H,m), 2.53(3H,s), 3.98(3H,s),4.12(2H,d,J=7.3 Hz), 7.32(2H,d,J=8.8 Hz), 7.73(2H,d,J=8.8 Hz),8.23(1H,s). IR (KBr) cm⁻¹: 1714,1672,1601,1502,1268,1251. Mass (m/z):332 (M⁺).

Example 15 Preparation of4-Ethoxycarbonyl-6-(4-methoxyphenyl)-2-(3-methyl-2-butenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and1-bromo-3-methyl-2-butene as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 87.6%.

Oil; ¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 1.75(3H,s), 1.86(3H,s),3.86(3H,s), 4.44(2H,q,J=7.1 Hz), 4.87(2H,d,J=7.1 Hz), 5.43-5.52(1H,m),6.99(2H,d,J=8.9 Hz), 7.75(2H,d,J=8.9 Hz), 8.16(1H,s). IR (KBr) cm⁻¹:1745,1713,1668,1609,1519,1309,1260,1181, 1134,1022,835. Mass (m/z): 342(M⁺).

Example 16 Preparation of2-Cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneUsing 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and(chloromethyl)cyclopropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 89.6%.

Pale yellow needles (chloroform-hexane); Melting point: 80.1-80.9° C.;¹H-NMR (CDCl3) δ: 0.46-0.59(4H,m), 1.40-1.51(4H,m), 3.87(3H,s),4.14(2H,d,J=7.3 Hz), 4.44(2H,q,J=7.1 Hz), 6.99(2H,d,J=9.0 Hz),7.75(2H,d,J=9.0 Hz), 7.47-7.51(2H,m), 8.18(1H,s). IR (KBr) cm⁻¹:1715,1706,1664,1598,1389,1273,1128,1114, 1020,828. Mass (m/z): 328 (M⁺).

Example 17 Preparation of2-Cyclopropylmethyl-6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and(chloromethyl)cyclopropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 78.7%.

Yellow needles (chloroform-hexane); Melting point: 136.5-137.3° C.;¹H-NMR (CDCl₃) δ: 0.46-0.62(4H,m), 1.39-1.52(1H,m), 3.94(3H,s),3.97(3H,s), 3.99(3H,s), 4.16(2H,d,J=7.3 Hz), 6.94(1H,d,J=8.3 Hz),7.33(1H,dd,J=2.2,8.3 Hz), 7.39(1H,d,J=2.2 Hz), 8.23(1H,s). IR (Kbr)cm⁻¹: 1709,1664,1525,1431,1300,1248,1229,1176, 1120,1026,1020. Mass(m/z): 344 (M⁺).

Example 18 Preparation of2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneand (chloromethyl)cyclopropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 54.7%.

Yellow needles (chloroform-hexane); Melting point: 113.6-116.6° C.;¹H-NMR (CDCl₃) δ: 0.44-0.62(4H,m), 1.37-1.52(1H,m), 3.95(3H,s),3.98(3H,s), 4.14(2H,d,J=7.3 Hz), 7.00-7.07(1H,m), 7.48-7.53(1H,m),7.58-7.64(1H,m), 8.21(1H,s). IR (KBr) cm⁻¹:1721,1660,1521,1437,1295,1275,1258,1106, 1023.

Example 19 Preparation of6-(3-Chloro-4-methoxyphenyl)-2-cyclopropylmethyl-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneand (chloromethyl)cyclopropane as starting materials, the procedure ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 72.7%.

Pale yellow needles (chloroform-hexane); Melting point: 101.4-103.8° C.;¹H-NMR (CDCl₃) δ: 0.45-0.62(4H,m), 1.48-1.52(1H,m), 3.97(3H,s),3.99(3H,s), 4.15(2H,d,J=4.5 Hz), 7.01(1H,d,J=8.5 Hz),7.66(1H,dd,J=2.4,8.5 Hz), 7.87(1H,d,J=2.4 Hz), 8.21(1H,s). IR (KBr)cm⁻¹: 1718,1660,1602,1509,1293. Mass (m/z): 350 (M⁺), 348 (M⁺).

Example 20 Preparation of2-Cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and(chloromethyl)cyclopropane as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 61.5%.

Yellow needles (chloroform-hexane); Melting point: 100.2-101.8° C.;¹H-NMR (CDCl3) δ: 0.41-0.61(4H,m), 1.38-1.51(1H,m), 2.53(3H,s),3.98(3H,s), 4.15(2H,d,J=7.3 Hz), 7.32(2H,d,J=8.4 Hz), 7.73(2H,d,J=8.4Hz), 8.24(1H,s). IR (KBr) cm⁻¹: 1731,1668,1602,1328,1267,1249. Mass(m/z): 330 (M⁺).

Example 21 Preparation of2-Cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one andcyclopentylmethyl methanesulfonate as starting materials, the proceduresof Example 1 were repeated likewise, whereby the title compound wasobtained in a yield of 88.5%.

Pale yellow needles (chloroform-hexane); Melting point: 63.6-64.4° C.;¹H-NMR (CDCl₃) δ: 1.26-1.46(5H,m), 1.49-1.81(6H,m), 2.50-2.66(1H,m),3.87(3H,s), 4.23(2H,d,J=7.6 Hz), 4.44(2H,q,J=7.1 Hz), 6.99(2H,d,J=8.8Hz), 7.75(2H,d,J=8.8 Hz), 8.17(1H,s). IR (KBr) cm⁻¹:1708,1667,1601,1518,1388,1272,1178, 1130,1114,1027,827,794. Mass (m/z):356 (M⁺).

Example 22 Preparation of2-Benzyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one andbenzyl bromide as starting materials, the procedures of Example 1 wererepeated likewise, whereby the title compound was obtained in a yield of96.9%.

Pale yellow crystals; ¹H-NMR (CDCl₃) δ: 3.86(3H,s), 3.96(3H,s),5.43(2H,s), 6.98(2H,d,J=9.1 Hz), 7.28-7.37(3H,m), 7.47-7.55(2H,m),7.75(2H,d,J=9.1 Hz), 8.22(1H,s). Mass (m/z): 350 (M⁺).

Example 23 Preparation of2-Benzyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzylbromide as starting materials, the procedures of Example 1 were repeatedlikewise, whereby the title compound was obtained in a yield of 75.3%.

Pale yellow crystals; ¹H-NMR (CDCl₃) δ: 1.41(3H,t,J=7.1 Hz), 3.86(3H,s),4.42(2H,q,J=7.1 Hz), 5.43(2H,s), 6.98(2H,d,J=9.0 Hz), 7.26-7.36(3H,m),7.50-7.55(2H,m), 7.75(2H,d,J=9.0 Hz), 8.17(1H,s).

Example 24 Preparation of2-(2,4-Dichlorobenzyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and2,4-dichlorobenzyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 88.3%.

Yellow needles (chloroform-hexane); Melting point: 135.7-136.3° C.;¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.86(3H,s), 4.44(2H,q,J=7.1 Hz),5.54(2H,s), 6.98(2H,d,J=8.9 Hz), 7.20(1H,dd,J=2.2,8.3 Hz),7.29(1H,d,J=8.3 Hz), 7.43(1H,d,J=2.2 Hz), 7.71(2H,d,J=8.9 Hz),8.22(1H,s). IR (KBr) cm⁻¹: 1748,1719,1664,1608,1518,1311,1254,1242,1163,1136,1026,836. Mass (m/z): 436 (M⁺), 434 (M⁺), 432 (M⁺).

Example 25 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and4-nitrobenzyl chloride as starting materials, the procedures of Example1 were repeated likewise, whereby the title compound was obtained in ayield of 92.6%.

Yellow fine needles (chloroform-hexane); Melting point: 215.4-216.6° C.;¹H-NMR (CDCl₃) δ: 3.87(3H,s), 3.97(3H,s), 5.50(2H,s), 7.00(2H,d,J=9.0Hz), 7.67(2H,d,J=8.8 Hz), 7.74(2H,d,J=9.0 Hz), 8.20(2H,d,J=8.8 Hz),8.26(1H,s). IR (KBr) cm⁻¹: 1720,1663,1601,1522,1347,1255. Mass (m/z):395 (M⁺).

Example 26 Preparation of2-(4-Aminobenzyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of4-methoxycarbonyl-6-(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-one(100 mg, 0.25 mmol) in methanol (30 m), 10% palladium on charcoal (40mg) was added, followed by catalytic reduction at room temperature underatmospheric pressure. Thirty minutes later, the catalyst was filteredoff. The methanol was distilled off under reduced pressure. The residuewas crystallized from chloroform-diethyl ether-hexane, whereby the titlecompound (91 mg, 98.5%) was obtained as yellow fine needles.

Melting point: 160.0-161.9° C.; ¹H-NMR (CDCl₃) δ: 3.65(2H,br),3.87(3H,s), 3.95(3H,s), 5.31(2H,s), 6.63(2H,d,J=8.4 Hz), 6.98(2H,d,J=8.8Hz), 7.36(2H,d,J=8.4 Hz), 7.75(2H,d,J=8.8 Hz), 8.19(1H,s). IR (KBr)cm⁻¹: 3417,3331,1741,1646,1611,1595,1517,1286, 1256,1181. Mass (m/z):365 (M⁺).

Example 27 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-[4-(3-pyridylcarbonylamino)benzyl]-2H-pyridazin-3-one

To a suspension of nicotinic acid (38 mg, 0.31 mmol) in tetrahydrofuran(2 ml), N-[3-(dimethylamino)-propyl]-N′-ethylcarbodiimide.hydrochloride(WSC.HCl) (60 mg,0.31 mmol) was added at room temperature, followed bystirring for 5 minutes. A solution of2-(4-aminobenzyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(76 mg, 0.21 mmol) in tetrahydrofuran (2 ml) was then added, followed bystirring at the same temperature for 13 hours. The solvent was distilledoff under reduced pressure, and the residue was dissolved in chloroform(30 ml). The solution was washed successively with water (30 ml) and asaturated aqueous solution of sodium chloride (brine) (30 ml), and wasthen dried over anhydrous sodium sulfate. The solvent was distilled offunder reduced pressure. The residue was separated and purified by silicagel preparative chromatography [developer: chloroform/methanol (10/1)],followed by crystallization from chloroform-hexane. The title compound(78 mg, 79.7%) was obtained as yellow prisms.

Melting point: 235.7-236.9° C. (dec.); ¹H-NMR (CDCl₃) δ: 3.87(3H,s),3.92(3H,s), 5.42(2H,s), 7.00(2H,d,J=9.0 Hz), 7.40-7.46(1H,m),7.56(2H,d,J=8.5 Hz), 7.63(2H,d,J=8.5 Hz), 7.76(2H,d,J=9.0 Hz),8.07(1H,br), 8.19-8.25(2H,m), 8.75-8.78(1H,m), 8.99-9.12(1H,s). IR (KBr)cm⁻¹: 3303,3266,1740,1668,1640,1606,1542,1518, 1412,1321,1253. Mass(m/z): 470 (M⁺)

Example 28 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and3-(chloromethyl)pyridine hydrochloride as starting materials, theprocedures of Example 1 were repeated likewise, whereby the titlecompound was obtained in a yield of 38.5%.

Pale yellow needles (chloroform-ether-hexane); Melting point:112.3-115.3° C. (dec.); ¹H-NMR (CDCl₃) δ: 3.87(3H,s), 3.97(3H,s),5.44(2H,s), 6.99(2H,d,J=9.0 Hz), 7.24-7.30(1H,m), 7.74(2H,d,J=9.0 Hz),7.86-7.92(1H,m), 8.24(1H,s), 8.54-8.57(1H,m), 7.98-8.81(1H,m). IR (KBr)cm⁻¹: 1720,1665,1599,1518,1311,1270. Mass (m/z): 351 (M⁺).

Example 29 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and3-phenylpropyl bromide as starting materials, the procedures of Example1 were repeated likewise, whereby the title compound was obtained in ayield of 94.0%.

Yellow oil; ¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1Hz), 2.17-2.30(2H,m),2.74(2H,t,J=7.8 Hz), 3.86(3H,s), 4.33(2H,t,J=7.1 Hz), 4.44(2H,q,J=7.1Hz), 6.98(2H,d,J=8.9 Hz), 7.13-7.30(5H,m), 7.74(2H,d,J=8.9 Hz),8.14(1H,s). IR (film) cm⁻¹: 1744,1713,1664,1610,1519,1256,1180,1131,1021. Mass (m/z): 392 (M⁺). HRMS: Calcd. for C₂₃H₂₄N₂O₄ (Found):392.17358 (392.17107).

Example 30 Preparation of2-Cinnamyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one andcinnamyl bromide as starting materials, the procedures of Example 1 wererepeated likewise, whereby the title compound was obtained in a yield of92.1%.

Pale yellow oil; ¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.86(3H,s),4.45(2H,q,J=7.1 Hz), 5.03(2H,d,J=6.6 Hz), 6.46(1H,td,J=6.6,15.9 Hz),6.75(1H,d,J=15.9 Hz), 6.99(2H,d,J=9.0 Hz), 7.20-7.41(5H,m),7.76(2H,d,J=9.0 Hz), 8.19(1H,s). IR (film) cm⁻¹:1744,1713,1668,1609,1518,1309,1256, 1025,835.

Example 31 Preparation of2-(4-Chlorocinnamyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 85.7%.

Yellow needles (chloroform-hexane); Melting point: 127.0-127.9° C.;¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.87(3H,s), 4.45(2H,q,J=7.1 Hz),5.02(2H,td,J=1.0,6.6 Hz), 6.42(1H,td,J=6.6,15.9 Hz),6.69(1H,td,J=1.0,15.9 Hz), 6.99(2H,d,J=8.9 Hz), 7.26(2H,d,J=8.9 Hz),7.32(2H,d,J=8.9 Hz), 7.76(2H,d,J=8.9 Hz), 8.20(1H,s).1181,1149,1026,1015,831. Mass (m/z): 426 (M⁺), 424 (M⁺).

Example 32 Preparation of2-(4-Chlorocinnamyl)-6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Melting point: 117.5-118.7° C.; ¹H-NMR (CDCl₃) δ: 3.94(3H,s),3.95(3H,s), 3.99(3H,s), 5.03(2H,dd,J=1.0,6.6 Hz), 6.43(1H,td,J=6.6,15.9Hz), 6.70(1H,td,J=1.0,15.9 Hz), 6.94(1H,d,J=8.3 Hz), 7.27(2H,d,J=8.8Hz), 7.31(2H,d,J=8.8 Hz), 7.33(1H,dd,J=2.2,8.3 Hz), 7.38(1H,d,J=2.2 Hz),8.26(1H,s). IR (KBr) cm⁻¹: 3046,1704,1674,1516,1419,1247,1226,1151,1023,979. Mass (m/z): 442 (M⁺), 440 (M⁺).

Example 33 Preparation of2-(4-Chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Using 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneand 4-chlorocinnamyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 75.5%.

Pale yellow needles (chloroform-hexane); Melting point: 131.3-132.3° C.;¹H-NMR (CDCl₃) δ: 3.95(3H,s), 3.99(3H,s), 5.02(2H,dd,J=1.1,6.7 Hz),6.42(1H,td,J=6.7,15.9 Hz), 6.70(1H,td,J=1.1,15.9 Hz), 7.00-7.07(1H,m),7.28(2H,d,J=8.9 Hz), 7.31(2H,d,J=8.9 Hz), 7.48-7.53(1H,m),7.59-7.66(1H,m), 8.22(1H,s). IR (KBr) cm⁻¹:1725,1661,1654,1523,1319,1271,1129. Mass (m/z): 430 (M⁺), 428 (M⁺).

Example 34 Preparation of2-(4-Chlorocinnamyl)-6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

Using6-(3-chloro-4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 76.8%.

Yellow prisms (chloroform-hexane); Melting point: 179.7-181.6° C.;¹H-NMR (CDCl₃) δ: 3.97(3H,s), 3.99(3H,s), 5.02(2H,dd,J=1.1,6.7 Hz),6.42(1H,td,J=6.7,15.9 Hz), 6.71(1H,td,J=1.1,15.9 Hz), 7.01(1H,d,J=8.6Hz), 7.28(2H,d,J=8. 8 Hz), 7.31(2H,d,J=8.8 Hz), 7.66(1H,dd,J=2.2,8.6Hz), 7.88(1H,d,J=2.2 Hz), 8.22(1H,s). IR (KBr) cm⁻¹:1747,1652,1605,1508,1286,1260,1240. Mass (m/z): 446 (M⁺), 444 (M⁺).

Example 35 Preparation of2-(4-Chlorocinnamyl)-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and4-chlorocinnamyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 82.3%.

Yellow prisms (chloroform-hexane); Melting point: 123.3-126.2° C.;¹H-NMR (CDCl₃) δ: 2.53(3H,s), 3.98(3H,s), 5.03(2H,dd,J=1.1,6.7 Hz),6.43(1H,td,J=6.7,15.9 Hz), 6.70(1H,td,J=1.1,15.9 Hz), 7.27(2H,d,J=8.8Hz), 7.30(2H,d,J=8.8 Hz),7.32(2H,d,J=8.7 Hz), 7.73(2H,d,J=8.7 Hz),8.26(1H,s). IR (KBr) cm⁻¹: 1712,1666,1600,1502,1490,1270,1095,977. Mass(m/z): 428 (M⁺), 426 (M⁺).

Example 36 Preparation of 2-(2,4-Difluorocinnamyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and2,4-difluorocinnamyl chloride as starting materials, the procedures ofExample 1 were repeated likewise, whereby the title compound wasobtained in a yield of 92.0%.

Yellow oil; ¹H-NMR (CDCl₃) δ: 1.42(3H,t,J=7.1 Hz), 3.87(3H,s),4.45(2H,q,J=7.1 Hz), 5.04(2H,dd,J=1.0,6.6 Hz), 6.48(1H,dd,J=6.6,16.0Hz), 6.73-6.87(3H,m), 6.99(2H,d,J=8.9 Hz), 7.37-7.47(1H,m),7.76(2H,d,J=8.9 Hz), 8.20(1H,s). IR (film) cm⁻¹:3074,1745,1713,1668,1610,1519,1503, 1258,1141,1026,967. Mass (m/z): 426(M⁺). HRMS: Calcd. for C₂₃H₂₀F₂N₂O₄ (Found): 426.13908 (426.14058).

Example 37 Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-[4-(methylthio)phenylcarbamoylmethyl]-2H-pyridazin-3-one

(1) Preparation of 2-Bromo-4′-(methylthio)acetanilide

To a solution of 4-(methylthio)aniline (200 mg, 1.44 mmol) in chloroform(2 ml), a saturated aqueous solution of sodium hydrogencarbonate (2 ml)was added, followed by the dropwise addition of a solution ofbromoacetyl bromide (300 mg, 1.49 mmol) in chloroform (2 ml) under icecooling. The mixture was then stirred for 1 hour. The chloroform layerwas separated, washed successively with 2N hydrochloric acid (10 ml) andbrine (10 ml), and then dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, whereby the title compound(356 mg, 95.3%) was obtained as pale brown crystals.

(2) Preparation of4-Methoxycarbonyl-6-(4-methoxyphenyl)-2-[4-(methylthio)phenylcarbamoylmethyl]-2H-pyridazin-3-one

Using 4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and2-bromo-4′-(methylthio)acetanilide as starting materials, the proceduresof Example 1 were repeated likewise, whereby the title compound wasobtained in a yield of 90.0%.

Yellow prisms (chloroform-hexane); Melting point: 130.2-132.4° C.;¹H-NMR (CDCl₃) δ: 2.44(3H,s), 3.87(3H,s), 3.98(3H,s), 5.08(2H,s),6.98(2H,d,J=8.9 Hz), 7.19(2H,d,J=8.7 Hz), 7.46(2H,d,J=8.7 Hz),7.78(2H,d,J=8.9 Hz), 8.32(1H,s), 8.64(1H,br). IR (KBr) cm⁻¹:3273,1744,1702,1652,1598,1518,1250. Mass (m/z): 439 (M⁺).

Example 38 Preparation of2-Benzyl-4-carbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To 2-benzyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (73mg, 0.20 mmol), an ammonia-methanol solution (about 10% W/W, 3 ml) wasadded, followed by stirring at room temperature for 17 hours.Precipitated crystals were collected by filtration, whereby the titlecompound (59 mg, 90.7%) was obtained as colorless fine needles.

Melting point: 196.0-198.0° C.; ¹H-NMR (CDCl₃) δ: 3.87(3H,s),5.48(2H,s), 5.93(1H,brs), 6.99(2H,d,J=9.0 Hz), 7.30-7.40(3H,m),7.49(2H,dd,J=2.0,8.1 Hz), 7.83(2H,d,J=9.0 Hz), 8.67(1H,s), 9.41(1H,br).IR (KBr) cm⁻¹: 3157,1703,1518,1391,1255,1034,830,729.

Example 39 Preparation of4-Carbamoyl-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 38 were repeatedlikewise, whereby the title compound was obtained in a yield of 90.5%.

Slightly yellow prisms (methanol-diethyl ether); Melting point:182.2-183.3° C.; ¹H-NMR (CDCl₃) δ: 0.47-0.62(4H,m), 1.40-1.51(1H,m),3.87(3H,s), 4.19(2H,d,J=7.3 Hz), 5.95(1H,br), 7.00(2H,d,J=8.8 Hz),7.82(2H,d,J=8.8 Hz), 8.68(1H,s), 9.50(1H,br). IR (KBr) cm⁻¹:3322,3161,1694,1610,1519,1419,1386,1269, 1252,1184,1024, 839. Mass(m/z): 299 (M⁺).

Example 40 Preparation of4-Carbamoyl-2-cyclopentylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 38 were repeatedlikewise, whereby the title compound was obtained in a yield of 91.5%.

Colorless needles (chloroform-hexane); Melting point: 182.2-183.3° C.;¹H-NMR (CDCl₃) δ: 1.31-1.46(2H,m), 1.50-1.83(6H,m), 2.48-2.65(1H,m),3.87(3H,s), 4.28(2H,d,J=7.6 Hz), 5.94(1H,br), 7.00(2H,d,J=8.9 Hz),7.82(2H,d,J=8.9 Hz), 8.67(1H,s), 9.51(1H,br). IR (KBr) cm⁻¹:3350,3158,1701,1517,1457,1389,1254,1189, 1177, 1131,1033,828,799. Mass(m/z): 327 (M⁺).

Example 41 Preparation of4-Carbamoyl-2-cinnamyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 2-cinnamyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 38 were repeatedlikewise, whereby the title compound was obtained in a yield of 40.0%.

Colorless fine needles (chloroform-diethyl ether); Melting point:184.0-186.0° C.; ¹H-NMR (CDCl₃) δ: 3.87(3H,s), 5.08(2H,dd,J=1.0,6.6 Hz),5.93(1H,brs), 6.44(1H,td,J=6.6,15.9 Hz), 6.75(1H,td,J=1.0,15.9 Hz),6.99(2H,d,J=8.9 Hz), 7.24-7.43(5H,m), 7.83(2H,d,J=9.0 Hz), 8.69(1H,s),9.44(1H,br). IR (KBr) cm⁻¹: 3347,3148,1704,1633,1610,1517,1391,1254,1034,829.

Example 42 Preparation of4-Carbamoyl-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 38 were repeatedlikewise, whereby the title compound was obtained in a yield of 96.6%.

Pale yellow fine needles (chloroform-hexane); Melting point:195.1-195.5° C.; ¹H-NMR (CDCl₃) δ: 3.87(3H,s), 5.07(2H,td,J=1.0,6.6 Hz),5.98(1H,br), 6.42(1H,td,J=6.6,15.8 Hz), 6.69(1H,td,J=1.0,15.8 Hz),6.99(2H,d,J=8.9 Hz), 7.27(2H,d,J=8.6 Hz), 7.33(2H,d,J=8.6 Hz),7.83(2H,d,J=8.9 Hz), 8.69(1H,s), 9.43(1H,br). IR (KBr) cm⁻¹:3324,3142,1702,1611,1570,1518,1491, 1388,1257,1169,1034,831. Mass (m/z):397 (M⁺), 395 (M⁺).

Example 43 Preparation of2-Isobutyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

To 4-ethoxycarbonyl-2-isobutyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(40 mg, 0.13 mmol), a 30% methylamine-ethanol (2 ml) was added, followedby stirring at room temperature for 30 minutes. The solvent wasdistilled off under reduced pressure and the residue was crystallizedfrom chloroform-hexane, whereby the title compound (35 mg, 91.9%) wasobtained as colorless needles.

Melting point: 124.9-125.2° C.; ¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.6 Hz),2.37-2.44(1H,m), 3.02(3H,d,J=5.3 Hz), 3.87(3H,s), 4.15(2H,d,J=7.3 Hz),6.99(2H,d,J=8.9 Hz), IR (KBr) cm⁻¹: 3244,1686,1590,1253,1184,1026,834.Mass (m/z): 315 (M⁺).

Example 44 Preparation of6-(4-Methoxyphenyl)-2-methyl-4-methylcarbamoyl-2H-pyridazin-3 -one

Using 2-methoxycarbonyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 95.3%.

Slightly yellow needles (chloroform-hexane); Melting point: 150.5-150.7°C.; ¹H-NMR (CDCl₃) δ: 3.03(3H,d,J=5.0 Hz), 3.87(3H,s), 3.95(3H,s),6.99(2H,d,J=8.9 Hz), 7.82(2H,d,J=8.9 Hz), 8.68(1H,s), 9.67(1H,br). IR(KBr) cm⁻¹: 3248,1679,1625,1610,1517,1459,1284,1249, 1185,1004,838.

Example 45 Preparation of2-Ethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using 2-ethyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 82.8%.

Slightly yellow needles (chloroform-hexane); Melting point: 122.4-122.9°C.; ¹H-NMR (CDCl₃) δ: 1.50(3H,t,J=7.3 Hz), 3.03(3H,d,J=5.0 Hz),3.87(3H,s), 4.38(2H,q,J=7.3 Hz), 7.00(2H,d,J=8.9 Hz), 7.83(2H,d,J=8.9Hz), 8.67(1H,s), 9.72(1H,br). IR (KBr) cm⁻¹:3241,1674,1567,1553,1517,1415,1251,1183, 1025. Mass (m/z): 287 (M⁺).

Example 46 Preparation of2-Cyanomethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-cyanomethyl-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 82.8%.

Pale brown prisms (chloroform-hexane); Melting point: 153.4-154.9° C.;¹H-NMR (CDCl₃) δ: 3.04(3H,t,J=5.3 Hz), 3.88(3H,s), 5.16(2H,s),7.01(2H,d,J=8.9 Hz), 7.83(2H,d,J=8.9 Hz), 8.74(1H,s), 9.28(1H,br). IR(KBr) cm⁻¹: 3292,2261,1690,1679,1554,1517,1257. Mass (m/z): 298 (M⁺).

Example 47 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-methylcarbamoylmethyl-2H-pyridazin-3-one

(1) Preparation of4-Ethoxycarbonyl-2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethylbromoacetate as starting materials, the procedures of Example 1 wererepeated likewise, whereby the title compound was obtained in a yield of84.5%.

Pale yellow needles (chloroform-diethyl ether-hexane); Melting point:77.1-77.8° C.; ¹H-NMR (CDCl₃) δ: 1.29(3H,t,J=7.1 Hz), 1.41(3H,t,J=7.1Hz), 3.8.6(3H,s), 4.26(2H,q,J=7.1 Hz), 4.43(2H,q,J=7.1 Hz), 4.99(2H,s),6.98(2H,d,J=8.9 Hz), 7.73(2H,d,J=8.9 Hz), 8.25(1H,s). IR (KBr) cm⁻¹:1754,1718,1675,1607,1518,1313,1284,1264, 1217,1159,1030,1018,842,794.Mass (m/z): 360 (M⁺).

(2) Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-methylcarbamoylmethyl-2H-pyridazin-3-one

Using4-ethoxycarbonyl-2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 84.5%.

Colorless fine needles; Melting point: 250.1-250.8° C.; ¹H-NMR (CDCl₃)δ: 2.87(3H,d,J=4.6 Hz), 2.99(3H,d,J=5.0 Hz), 3.87(3H,s), 4.95(2H,s),6.14(2H,br), 6.98(2H,d,J=9.1 Hz), 7.82(2H,d,J=9.1 Hz), 8.70(1H,s),9.44(1H,br). IR (KBr) cm⁻¹: 3293,3114,1683,1666,1516,1252,1164,1026,834,798. Mass (m/z): 330 (M⁺).

Example 48 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-vinyl-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-vinyl-2H-pyridazin-3-one asa starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 36.7%.

Yellow needles (chloroform-hexane); Melting point: 130.3-132.8° C.;¹H-NMR (CDCl₃) δ: 3.03(3H,d,J=5.0 Hz), 3.88(3H,s), 5.18(1H,d,J=8.6 Hz),6.03(1H,d,J=15.4 Hz), 7.01(2H,d,J=9.0 Hz), 7.85(1H,dd,J=8.6,15.4 Hz), IR(KBr) cm⁻¹: 3238,3121,1683,1632,1607,1548,1516,1411,1314,1272,1245,1180.

Example 49 Preparation of2-(2-Hydroxyethyl)-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using4-ethoxycarbonyl-2-(2-hydroxyethyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 97.2%.

Pale yellow needles (chloroform-hexane); Melting point: 160.3-160.6° C.;¹H-NMR (CDCl₃) δ: 2.87(1H,brt,J=5.7 Hz), 3.00(3H,d,J=5.1 Hz),3.87(3H,s), 4.17-4.19(2H,m), 4.51-4.56(2H,m), 7.00(2H,d,J=8.9 Hz),7.80(2H,d,J=8.9 Hz), 8.69(1H,s), 9.57(1H,br). IR (KBr) cm¹:3462,3228,1671,1619,1592,1536,1519,1265, 1187,1070,833. Mass (m/z): 303(M⁺).

Example 50 Preparation of2-(2-Cyanoethyl)-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-(2-cyanoethyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting likewise, whereby the title compound was obtained in ayield of 90.3%.

Pale yellow fine needles (chloroform-hexane); Melting point:164.5-167.2° C. (dec.); ¹H-NMR (CDCl₃) δ: 2.99(2H,t,J=6.7 Hz),3.03(3H,d,J=5.0 Hz), 3.87(3H,s), 4.59(2H,t,J=6.9 Hz), 7.00(2H,d,J=8.6Hz), 7.83(2H,d,J=8.6 Hz), 8.71(1H,s), 9.44(1H,br). IR (KBr) cm⁻¹:2246,1717,1664,1520,1275,1250. Mass (m/z): 312 (M⁺).

Example 51 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-n-propyl-2H-pyridazin-3-one

Using4-methoxycarbonyl-6-(4-methoxyphenyl)-2-n-propyl-2H-pyridazin-3-one as astarting material, the procedures of Example 43 were repeated likewise,whereby the title compound was obtained in a yield of 85.3%.

Colorless needles (chloroform-hexane); Melting point: 106.5-107.1° C.;¹H-NMR (CDCl₃) δ: 1.02(3H,t,J=7.3 Hz), 1.85-2.00(2H,m), 3.02(3H,d,J=5.0Hz), 3.87(3H,s), 4.29(2H,t,J=7.3 Hz), 6.99(2H,d,J=8.9 Hz),7.82(2H,d,J=8.9 Hz), 8.66(1H,s), 9.72(1H,br). Mass (m/z): 301 (M⁺).

Example 52 Preparation of2-Isopropyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using4-ethoxycarbonyl-2-isopropyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 43 were repeated likewise,whereby the title compound was obtained in a yield of 91.9%.

Colorless needles (chloroform-hexane); Melting point: 154.0-154.3° C.;¹H-NMR (CDCl₃) δ: 1.47(6H,d,J=6.6 Hz), 3.03(3H,d,J=5.0 Hz), 3.87(3H,s),5.36-5.52(1H,m), 7.00(2H,d,J=8.9 Hz), 7.85(2H,d,J=8.9 Hz), 8.66(1H,s),9.77(1H,br). IR (KBr) cm⁻¹: 3262,1677,1547,1518,1417,1310,1269,1250,1175,1021,831,801. Mass (m/z): 301 (M⁺).

Example 53 Preparation of6-(3,4-Dimethoxyphenyl)-2-isobutyl-4-methylcarbamoyl-2H-pyridazin-3-one

Using4-ethoxycarbonyl-6-(3,4-dimethoxyphenyl)-2-isobutyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.8%.

Slightly yellow needles (chloroform-hexane); Melting point: 111.4-112.6°C.; ¹H-NMR (CDCl₃) δ: 1.01(6H,d,J=6.6 Hz), 2.28-2.43(1H,m),3.03(3H,d,J=5.0 Hz), 3.95(3H,s), 3.97(3H,s), 4.16(2H,d,J=7.3 Hz),6.96(1H,d,J=8.6 Hz), 7.41-7.46(2H,m), 8.68(1H,s), 9.72(1H,br). IR (KBr)cm⁻¹: 3276,1683,1585,1551,1512,1257,1227,1171, 1118,1021,871. Mass(m/z): 345 (M⁺).

Example 54 Preparation of6-(3-Fluoro-4-methoxyphenyl)-2-isobutyl-4-methylcarbamoyl-2H-pyridazin-3-one

Using6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 88.3%.

Pale yellow needles (chloroform-hexane); Melting point: 153.3-154.9° C.;¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.6 Hz), 2.27-2.43(1H,m), 3.02(3H,d,J=5.0Hz), 3.95(3H,s), 4.15(2H,d,J=7.3 Hz), 7.00-7.08(1H,m), 7.55-7.61(1H,m),7.65-7.72(1H,m), 9.68(1H,br). IR (KBr) cm⁻¹:3248,1684,1522,1509,1435,1297,1276. Mass (m/z): 333 (M⁺).

Example 55 Preparation of6-(3-Chloro-4-methoxyphenyl)-2-isobutyl-4-methylcarbamoyl-2H-pyridazin-3-one

Using6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.3%.

Slightly yellow needles (chloroform-hexane); Melting point: 181.8-183.5°C.; ¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.6 Hz), 2.27-2.43(1H,m),3.02(3H,d,J=5.0 Hz), 3.97(3H,s), 4.15(2H,d,J=7.3 Hz), 7.01(1H,d,J=8.6Hz), 7.72(1H,dd,J=2.3,8.6 Hz), 7.85(1H,d,J=2.3 Hz), 8.64(1H,s),9.68(1H,br). IR (KBr) cm⁻¹: 3248,1685,1546,1509,1410,1294,1264. Mass(m/z): 351 (M⁺), 349 (M⁺).

Example 56 Preparation of2-Isobutyl-4-methylcarbamoyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using2-isobutyl-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.3%.

Slightly yellow needles (chloroform-hexane); Melting point: 129.6-130.6°C.; ¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.6 Hz), 2.27-2.43(1H,m), 2.53(3H,s),3.02(3H,d,J=4.9 Hz), 4.16(2H,d,J=7.3 Hz), 7.33(2H,d,J=8.7 Hz),7.80(2H,d,J=8.7 Hz), 8.68(1H,s), 9.69(1H,br). IR (KBr) cm⁻¹:3275,1687,1624,1575,1506,1400,1394. Mass (m/z): 331 (M⁺).

Example 57 Preparation of6-(4-Methoxyphenyl)-2-(3-methyl-2-butenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-(3-methyl-2-butenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 79.0%.

Slightly yellow needles (chloroform-hexane); Melting point: 103.6-104.0°C.; ¹H-NMR (CDCl₃) δ: 1.77(3H,s), 1.88(3H,s), 3.02(3H,d,J=5.0 Hz),3.87(3H,s), 4.90(2H,d,J=7.3 Hz), 5.41-5.50(1H,m), 6.99(2H,d,J=8.9 Hz),7.82(2H,d,J=8.9 Hz), 8.66(1H,s), 9.71(1H,br). IR (KBr) cm⁻¹:3244,1675,1546,1517,1248,1175,1025,831, 798. Mass (m/z): 327 (M⁺).

Example 58 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-(2-pyridylmethyl)carbamoylmethyl-2H-pyridazin-3-one

(1) Preparation of6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 43 were repeated likewise,whereby the title compound was obtained in a yield of 97.9%.

Colorless needles (chloroform-hexane); Melting point: 246.5-246.9° C.;¹H-NMR (CDCl₃) δ: 3.06(3H,d,J=5.0 Hz), 3.87(3H,s), 7.00(2H,d,J=8.9 Hz),7.83(2H,d,J=8.9 Hz), 8.74(1H,s), 9.46(1H,br), 11.89(1H,br). IR (KBr)cm⁻¹: 3219,3142,1675,1568,1518,1257,1226,1184, 1032,832. Mass (m/z): 259(M⁺).

(2) Preparation of2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using 6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one as astarting material, the procedures or Example 47-(1) were repeatedlikewise, whereby the title compound was obtained in a yield of 98.5%.

Melting point: 141.0-142.2° C.; ¹H-NMR (CDCl₃) δ: 1.31(3H,t,J=7.3 Hz),3.01(3H,d,J=5.0 Hz), 3.87(3H,s), 4.28(2H,q,J=7.3 Hz), 5.02(2H,s),6.99(2H,d,J=8.9 Hz), 7.81(2H,d,J=8.9 Hz), 8.72(1H,s), 9.47(1H,br). IR(KBr) cm⁻¹: 3283,1735,1691,1508,1259,1226,1169,1028. Mass (m/z): 345(M⁺).

(3) Preparation of6-(4-methoxyphenyl)-4-methylcarbamoyl-2-(2-pyridylmethyl)carbamoylmethyl-2H-pyridazin-3-one

In xylene,2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-oneand 2-(aminomethyl)pyridine were refluxed at 150° C. for 7 hours.Post-treatments were conducted as in Example 47-(2), whereby the titlecompound was obtained in a yield of 44.5%.

Slightly yellow prisms (chloroform-hexane); Melting point: 194.7-195.8°C.; ¹H-NMR (CDCl₃) δ: 3.00(3H,t,J=5.0 Hz), 3.87(3H,s), 4.62(2H,d,J=5.0Hz), 5.06(2H,s), 6.98(2H,d,J=8.9 Hz), 7.15-7.21(1H,m), 7.33-7.38(1H,m),7.35(1H,brt,J=5.0 Hz), 7.61-7.69(1H,m), 7.83(2H,d,J=8.9 Hz),8.43-8.47(1H,m), 8.72(1H,s), 9.49(1H,br). IR (KBr) cm⁻¹:3283,1681,1664,1518,1251,1167,1024. Mass (m/z): 407 (M⁺).

Example 59 Preparation of2-(2-Hydroxyethyl)carbamoylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

In methanol,2-ethoxycarbonylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-oneand 2-aminoethanol were heated under reflux for 4 hours. Post-treatmentswere conducted as in Example 43, whereby the title compound was obtainedin a yield of 91.0%.

Colorless fine needles (chloroform-hexane); Melting point: 240.2-241.2°C.; ¹H-NMR (CDCl₃) δ: 2.34(1H,t,J=5.7 Hz), 2.98(3H,d,J=5.1 Hz),3.46-3.53(2H,m), 3.72-3.80(2H,m), 3.87(3H,s), 4.98(2H,s), 6.52(1H,br),6.99(2H,d,J=8.9 Hz), 7.82(2H,d,J=8.9 Hz), 8.70(1H,s), 9.42(1H,br). IR(KBr) cm⁻¹: 3405,3288,1675,1657,1574,1554,1519,1508,1416,1402,1253,1074,835. Mass (m/z): 360 (M⁺).

Example 60 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-[4-(methylthio)phenylcarbamoylmethyl]-2H-pyridazin-3-one

Using4-methoxycarbonyl-6-(4-methoxyphenyl)-2-[4-(methylthio)phenylcarbamoylmethyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.2%.

Slightly yellow prisms (chloroform-hexane); Melting point: 230.6-232.0°C.; ¹H-NMR (CDCl₃) δ: 2.46(3H,s), 3.03(3H,d,J=5.0 Hz), 3.87(3H,s),3.98(3H,s), 5.10(2H,s), 6.99(2H,d,J=9.1 Hz), 7.23(2H,d,J=8.7 Hz),7.46(2H,d,J=8.7 Hz), 7.84(2H,d,J=9.1 Hz), 8.16(1H,br), 8.74(1H,s),9.42(1H,br). IR (KBr) cm⁻¹: 3290,3236,1680,1539,1518,1254. Mass (m/z):438 (M⁺).

Example 61 Preparation of2-Cyclopropylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 89.1%.

Slightly yellow needles (methanol-diethyl ether); Melting point:136.6-137.5° C.; ¹H-NMR (CDCl₃) δ: 0.47-0.62(4H,m), 1.39-1.49(1H,m),3.03(3H,d,J=5.1 Hz), 3.87(3H,s), 4.18(2H,d,J=7.3 Hz), 7.00(2H,d,J=8.9Hz), 7.83(2H,d,J=8.9 Hz), 8.67(1H,s), 9.72(1H,brd,J=5.1 Hz). IR (KBr) cm¹ 3339,1684,1627,1609,1518,1252,1183,1027, 845,836,811. Mass (m/z): 313(M⁺).

Example 62 Preparation of2-Cyclopropylmethyl-6-(3,4-dimethoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopropylmethyl-6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 95.3%.

Pale yellow needles (chloroform-hexane); Melting point: 156.1-154.1° C.;¹H-NMR (CDCl₃) δ: 0.47-0.65(4H,m), 1.38-1.51(1H,m), 3.03(3H,d,J=5.0 Hz),3.95(3H,s), 3.97(3H,s), 4.19(2H,d,J=7.3 Hz), 6.96(1H,d,J=8.9 Hz),7.43(1H,d,J=2.3 Hz), 7.44(1H,dd,J=2.3,8.9 Hz), 8.69(1H,s), 9.72(1H,br).IR (KBr) cm⁻¹: 3267,1686,1552,1520,1508,1422,1255,1232, 1034. Mass(m/z): 343 (M⁺).

Example 63 Preparation of2-Cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 90.3%.

Pale yellow needles (chloroform-hexane); Melting point: 139.6-140.7° C.;¹H-NMR (CDCl₃) δ: 0.45-0.64(4H,m), 1.36-1.51(1H,m), 3.03(3H,d,J=5.0 Hz),3.96(3H,s), 4.18(2H,d,J=7.3 Hz), 7.01-7.08(1H,m), 7.56-7.61(1H,m),7.65-7.72(1H,m), 8.66(1H,s), 9.69(1H,br). IR (KBr) cm⁻¹:3281,1688,1523,1510,1436,1299,1275. Mass (m/z): 331 (M⁺).

Example 64 Preparation of6-(3-Chloro-4-methoxyphenyl)-2-cyclopropylmethyl-4-methylcarbamoyl-2H-pyridazin-3-one

Using6-(3-chloro-4-methoxyphenyl)-2-cyclopropylmethyl-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 90.3%.

Slightly yellow needles (chloroform-hexane); Melting point: 172.4-173.4°C.; ¹H-NMR (CDCl₃) δ: 0.46-0.64(4H,m), 1.38-1.50(1H,m), 3.03(3H,d,J=5.3Hz), 3.97(3H,s), 4.18(2H,d,J=7.3 Hz), 7.02(1H,d,J=8.8 Hz),7.73(1H,dd,J=2.3,8.8 Hz), 7.95(1H,d,J=2.3 Hz), 8.65(1H,s), 9.68(1H,br).IR (KBr) cm⁻¹: 3244,1684,1552,1509,1410,1294,1264. Mass (m/z): 349 (M⁺),347 (M⁺).

Example 65 Preparation of2-Cyclopropylmethyl-4-methylcarbamoyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthiophenyl)]-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.3%.

Yellow prisms (chloroform-hexane); Melting point: 116.5-118.0° C.;.¹H-NMR (CDCl₃) δ: 0.45-0.64(4H,m), 1.36-1.51(1H,m), 2.53(3H,s),3.03(3H,d,J=4.9 Hz), 4.18(2H,d,J=7.3 Hz), 7.33(2H,d,J=8.7 Hz),7.80(2H,d,J=8.7 Hz), 8.69(1H,s), 9.69(1H,br). IR (KBr) cm⁻¹:3275,1686,1625,1595,1545,1505,1400. Mass (m/z): 329 (M⁺).

Example 66 Preparation of2-Cyclopropylmethyl-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneIn methanol,2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand 70% aqueous solution of ethylamine were reacted at 70° C. for 4hours. Post-treatments were conducted as in Example 43, whereby thetitle compound was obtained in a yield of 80.2%.

Colorless needles (chloroform-hexane); Melting point: 136.3-136.9° C.;¹H-NMR (CDCl₃) δ: 0.47-0.64(4H,m), 1.28(3H,t,J=7.3 Hz), 1.37-1.53(1H,m),3.51(2H,d,J=8.9 Hz), 3.87(3H,s), 4.18(2H,d,J=7.3 Hz), 7.00(2H,d,J=8.9Hz), 7.83(2H,d,J=8.9 Hz), 8.68(1H,s), 9.76(1H,brt,J=5.9 Hz). IR (KBr)cm⁻¹: 3211,1679,1622,1610,1517,1417,1249,1182, 1033,834. Mass (m/z): 327(M⁺).

Example 67 Preparation of2-Cyclopropylmethyl-6-(4-methoxyphenyl)-4-n-propylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand an n-propylaminemethanol solution as starting materials, theprocedures of Example 43 were repeated likewise, whereby the titlecompound was obtained in a yield of 65.4%.

Colorless needles (chloroform-hexane); Melting point: 101.3-101.6° C.;¹H-NMR (CDCl₃) δ: 0.46-0.63(4H,m), 1.01(3H,t,J=7.3 Hz), 1.39-1.52(1H,m),1.60-1.76(2H,m), 3.44(2H,d,J=6.9 Hz), 3.87(3H,s), 4.18(2H,d,J=7.3 Hz),7.00(2H,d,J=8.9 Hz), 7.83(2H,d,J=8.9 Hz), 8.68(1H,s), 9.81(1H,br). IR(KBr) cm⁻¹: 3216,1679,1622,1608,1517,1416,1252,1182, 1033,833. Mass(m/z): 341 (M⁺).

Example 68 Preparation of4-Benzylcarbamoyl-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneBenzylamine (318 mg, 2.97 mmol) was added to a solution of2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(65 mg, 0.20 mmol) in xylene (1 ml), followed by stirring at 140° C. for24 hours. The reaction mixture was added with ethyl acetate (20 ml),washed successively with 2N hydrochloric acid (20 ml) and brine (20 ml),and then dried over anhydrous sodium sulfate. The solvent was distilledoff and the residue (98 mg) was crystallized from chloroform-hexane,whereby the title compound (72 mg, 93.4%) was obtained as pale yellowfine needles.

Melting point: 119.7-120.1° C.; ¹H-NMR (CDCl₃) δ: 0.44-0.62(4H,m),1.37-1.50(1H,m), 3.89(3H,s), 4.16(2H,d,J=7.3 Hz), 4.67(2H,d,J=5.9 Hz),7.00(2H,d,J=8.8 Hz), 7.24-7.41(5H,m), 7.83(2H,d,J=8.8 Hz), 8.71(1H,s),10.18(1H,brt,J=5.9 Hz). IR (KBr) cm⁻¹:3210,1675,1622,1610,1516,1274,1250,1185, 1028,838. Mass (m/z): 389 (M⁺).

Example 69 Preparation of2-Cyclopropylmethyl-6-(4-methoxyphenyl)-4-(2-pyridylmethyl)carbamoyl-2H-pyridazin-3-one

In xylene,2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand 2-(aminomethyl)pyridine were reacted at 140° C. for 1 hour.Post-treatments were conducted as in Example 58-(3), whereby the titlecompound was obtained in a yield of 84.2%.

Slightly yellow needles (chloroform-hexane); Melting point: 98.6-99.3°C.; ¹H-NMR (CDCl₃) δ: 0.46-0.63(4H,m), 1.39-1.55(1H,m), 3.87(3H,s),4.20(2H,d,J=7.3 Hz), 4.83(2H,d,J=5.4 Hz), 7.00(2H,d,J=9.3 Hz),7.17-7.23(1H,m), 7.32-7.37(1H,m), 7.63-7.71(1H,m), 7.83(2H,d,J=9.3 Hz),8.61-8.65(1H,m), 8.71(1H,s), 10.55(1H,brt,J=5.4 Hz). IR (KBr) cm⁻¹:3252,1683,1624,1609,1516,1417,1273,1253, 1181,1022,834. Mass (m/z): 390(M⁺).

Example 70 Preparation of2-Cyclopropylmethyl-6-(4-methoxyphenyl)-4-(4-pyridyl)carbamoyl-2H-pyridazin-3-one

Sodium hydride (9 mg, 0.38 mmol; used after removal of oil by washing itwith toluene) was added to a solution of 4-aminopyridine (34 mg, 0.361mmol) in dimethylsulfoxide (0.5 ml), followed by stirring at roomtemperature for 15 minutes. Thereafter,2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(80 mg, 0.24 mmol) was added, followed by stirring at the sametemperature for 30 minutes. The reaction mixture was added with ethylacetate (30 ml), washed successively with water (20 ml) and brine (20ml), and then dried over anhydrous sodium sulfate. The solvent wasdistilled off and the residue (61 mg) was separated and purified bysilica gel preparative chromatography [developer: chloroform/methanol(10/1)], whereby the title compound (61 mg, 61.1%) was obtained.

Pale yellow fine needles (chloroform-hexane); Melting point:181.3-181.5° C.; ¹H-NMR (CDCl₃) δ: 0.49-0.68(4H,m), 1.40-1.56(1H,m),3.89(3H,s), 4.24(2H,d,J=7.3 Hz), 7.02(2H,d,J=8.9 Hz), 7.69(2H,d,J=6.3Hz), 7.85(2H,d,J=8.9 Hz), 8.57(2H,d,J=6.3 Hz), 8.75(1H,s), 12.25(1H,br).IR (KBr) cm⁻¹: 1697,1629,1607,1517,1273,1254,1184,1017, 835,813,805,791. Mass (m/z): 376 (M⁺).

Example 71 Preparation of2-Cyclopropylmethyl-6-(4-methoxyphenyl)-4-phenylcarbamoyl-2H-pyridazin-3-one

2-Cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand aniline were processed as in Example 70, whereby the title compoundwas obtained in a yield of 12.2%.

Pale yellow fine needles (chloroform-hexane); Melting point:162.8-163.3° C. ¹H-NMR (CDCl₃) δ: 0.49-0.67(4H,m), 1.41-1.68(1H,m),3.88(3H,s), 4.23(2H,d,J=7.3 Hz), 7.01(2H,d,J=8.9 Hz), 7.13-7.20(1H,m),7.34-7.42(2H,m), 7.75-7.81(2H,m), 7.85(2H,d,J=8.9 Hz), 8.77(1H,s),12.00(1H,br). IR (KBr) cm⁻¹: 3189,1687,1602,1518,1274,1254,1184,1025,834,804,791. Mass (m/z): 375 (M⁺).

Example 72 Preparation of2-Cyclopentylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 75.2%.

Colorless needles (chloroform-hexane); Melting point: 107.4-107.8° C.;¹H-NMR (CDCl₃) δ: 1.30-1.45(2H,m), 1.50-1.82(6H,m), 2.47-2.64(1H,m),3.02(3H,d,J=5.0 Hz), 3.87(3H,s), 4.27(2H,d,J=7.6 Hz), 7.00(2H,d,J=8.9Hz), 7.83(2H,d,J=8.9 Hz), 8.66(1H,s), 9.74(1H,br). IR (KBr) cm⁻¹:3218,1679,1624,1611,1560,1550,1517,1414, 1249,1188,1138,1030,844,802.Mass (m/z): 341 (M⁺).

Example 73 Preparation of2-Cyclopentylmethyl-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

In methanol,2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand a 70% aqueous solution of ethylamine were processed as in Example43, whereby the title compound was obtained in a yield of 82.2%.

Colorless needles (chloroform-hexane); Melting point: 129.1-129.4° C.;¹H-NMR (CDCl₃) δ: 1.27(3H,t,J=7.3 Hz), 1.34-1.45(2H,m), 1.50-1.82(6H,m),2.48-2.65(1H,m), 3.44-3.56(2H,m), 3.87(3H,s), 4.27(2H,d,J=7.6 Hz),6.99(2H,d,J=8.9 Hz), 7.82(2H,d,J=8.9 Hz), 8.67(1H,s), 9.76(1H,br). IR(KBr) cm⁻¹: 3242,1683,1623,1609,1518,1417,1311,1249, 1181,1033,834,800.Mass (m/z): 355 (M⁺).

Example 74 Preparation of2-Cyclopentylmethyl-6-(4-methoxyphenyl)-4-n-propylcarbamoyl-2H-pyridazin-3-one

Using2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 67 were repeatedlikewise, whereby the title compound was obtained in a yield of 79.1%.

Colorless needles (chloroform-hexane); Melting point: 109.9-110.2° C.;¹H-NMR (CDCl₃) δ: 1.01(3H,t,J=7.3 Hz), 1.31-1.46(2H,m), 1.50-1.83(8H,m),2.48-2.65(1H,m), 3.44(2H,q,J=6.4 Hz), 3.87(3H,s), 4.27(2H,d,J=7.6 Hz),7.00(2H,d,J=8.9 Hz), 7.82(2H,d,J=8.9 Hz), 8.67(1H,s), 9.81(1H,br). IR(KBr) cm⁻¹: 3246,1683,1544,1519,1417,1311,1273,1252, 1030,835,797. Mass(m/z): 369 (M⁺).

Example 75 Preparation of4-Benzylcarbamoyl-2-cyclopentylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

In xylene,2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneand benzylamine were reacted at 140° C. for 2 hours. Post-treatmentswere conducted as in Example 68, whereby the title compound was obtainedin a yield of 78.5%.

Pale yellow needles (chloroform-hexane); Melting point: 107.6-108.1° C.;¹H-NMR (CDCl₃) δ: 1.28-1.44(2H,m), 1.48-1.81(6H,m), 2.46-2.63(1H,m),3.87(3H,s), 4.25(2H,d,J=7.6 Hz), 4.66(2H,d,J=5.9 Hz), 7.00(2H,d,J=8.9Hz), 7.23-7.40(5H,m), 7.82(2H,d,J=8.9 Hz), 8.70(1H,s),10.18(1H,brt,J=5.9 Hz). IR (KBr) cm⁻¹:3251,1677,1624,1611,1517,1386,1259,1179, 1136,1033,831. Mass (m/z): 417(M⁺).

Example 76 Preparation of2-Cyclopentylmethyl-6-(4-methoxyphenyl)-4-(2-pyridylmethyl)carbamoyl-2H-pyridazin-3-one

Using2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 58-(3) were repeatedlikewise, whereby the title compound was obtained in a yield of 88.6%.

Colorless needles (chloroform-hexane); Melting point: 126.6-127.5° C.;¹H-NMR (CDCl₃) δ: 1.30-1.46(2H,m), 1.49-1.82(6H,m), 2.50-2.67(1H,m),3.87(3H,s), 4.29(2H,d,J=7.6 Hz), 4.82(2H,d,J=5.3 Hz), 7.00(2H,d,J=8.9Hz), 7.16-7.23(1H,m), 7.31-7.36(1H,m), 7.62-7.70(1H,m), 7.83(2H,d,J=8.9Hz), 8.60-8.64(1H,m), 8.69(1H,s), 10.53(1H,brt,J=5.3 Hz). IR (KBr) cm⁻¹:3255,1673,1624,1610,1511,1457,1433,1259, 1251,1028,832. Mass (m/z): 418(M⁺).

Example 77 Preparation of4-Benzylcarbamoyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one

In xylene,4-ethoxycarbonyl-6-(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one andbenzylamine were reacted at 140° C. for 1 hour. Post-treatments wereconducted as in Example 68, whereby the title compound was obtained in ayield of 94.2%.

Pale yellow needles (chloroform-hexane); Melting point: 144.8-145.8° C.;¹H-NMR (CDCl₃) δ: 3.87(3H,s), 3.94(3H,s), 4.67(2H,d,J=5.9 Hz),7.00(2H,d,J=8.9 Hz), 7.23-7.40(5H,m), 7.82(2H,d,J=8.9 Hz), 8.71(1H,s),10.13(1H,brt,J=5.9 Hz). IR (KBr) cm⁻¹:3244,1679,1624,1583,1516,1455,1251,1182, 1030,836. Mass (m/z): 349 (M⁺).

Example 78 Preparation of6-(4-Methoxyphenyl)-2-methyl-4-(2-pyridylmethyl)carbamoyl-2H-pyridazin-3-one

Using 4-ethoxycarbonyl-2-methyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 58-(3) were repeatedlikewise, whereby the title compound was obtained in a yield of 86.1%.

Pale yellow needles (chloroform-hexane); Melting point: 122.4-122.9° C.;¹H-NMR (CDCl₃) δ: 3.87(3H,s), 3.97(3H,s), 4.82(2H,d,J=5.6 Hz),7.00(2H,d,J=8.9 Hz), 7.17-7.23(1H,m), 7.31-7.36(1H,m), 7.63-7.71(1H,m),7.82(2H,d,J=8.9 Hz), 8.61-8.65(1H,m), 8.71(1H,s), 10.53(1H,brt,J=5.6Hz). IR (KBr) cm⁻¹: 3238,1683,1625,1613,1516,1435,1248,1180, 1035,836.Mass (m/z): 350 (M⁺).

Example 79 Preparation of2-Benzyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one and2-benzyl-4-dimethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To 40% aqueous solution of dimethylamine (3 ml),2-benzyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (71 mg,0.19 mmol) was added, followed by stirring at room temperature for 17hours. The solvent was distilled off, and the residue (74 mg) wasseparated and purified by silica gel preparative chromatography[developer: chloroform/methanol (20/1)]. From fractions of large Rfvalues, the title compound[2-benzyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one](29.4 mg, 44.7%) was obtained. Pale yellow needles (chloroform-diethylether)

Melting point: 181.7-182.1° C.; ¹H-NMR (CDCl₃) δ: 3.00(3H,d,J=4.9 Hz),3.87(3H,s), 5.47(2H,s), 7.00(2H,d,J=8.8 Hz), 7.30-7.36(2H,m),7.47(2H,d,J=6.4 Hz), 7.84(2H,d,J=9.3 Hz), 8.67(1H,s), 9.65(1H,br). IR(KBr) cm⁻¹: 3270,1680,1607,1518,1408,1251,1026,850, 743.

From fractions of small Rf values, the title compound[2-benzyl-6-(4-methoxyphenyl)-4-(dimethylcarbamoyl)-2H-pyridazin-3-one](10.5 mg, 14.8%) was also obtained.

Colorless fine needles (chloroform-diethyl ether-hexane); Melting point:183.0-184.0° C.; ¹H-NMR (CDCl₃) δ: 2.96(3H,s), 3.11(3H,s), 3.86(3H,s),5.41(2H,s), 6.97(2H,d,J=9.0 Hz), 7.26-7.33(3H,m), 7.50(2H,dd,J=2.0,8.0Hz), 7.72(2H,d,J=9.0 Hz), 7.74(1H,s). IR (KBr) cm⁻¹:1654,1641,1610,1521,1250,1025,832.

Example 80 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-(4-nitrobenzyl)-2H-pyridazin-3-one

Using4-methoxycarbonyl-6-(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.2%.

Yellow needles (chloroform-hexane); Melting point: 198.8-199.4° C.;¹H-NMR (CDCl₃) δ: 3.01(3H,d,J=5.0 Hz), 3.88(3H,s), 5.54(2H,s),7.01(2H,d,J=9.2 Hz), 7.62(2H,d,J=8.9 Hz), 7.82(2H,d,J=9.2 Hz),8.22(2H,d,J=8.9 Hz), 8.71(1H,s), 9.48(1H,br). IR (KBr) cm⁻¹:3282,1680,1515,1344,1254. Mass (m/z): 394 (M⁺).

Example 81 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-[4-(3-pyridylcarbonylamino)benzyl]-2H-pyridazin-3-one

Using4-methoxycarbonyl-4-methylcarbamoyl-2-[4-(3-pyridylcarbonylamino)benzyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 92.7%.

Slightly yellow fine needles (chloroform-hexane); Melting point:226.7-227.6° C. (dec.); ¹H-NMR (CDCl₃) δ: 3.00(3H,d,J=5.0 Hz),3.87(3H,s), 5.46(2H,s), 7.00(2H,d,J=9.0 Hz), 7.44(1H,ddd,J=1.1,4.6,6.8Hz), 7.53(2H,d,J=8.5 Hz), 7.63(2H,d,J=8.5 Hz), 7.83(2H,d,J=9.0 Hz),7.87(1H,br), 8.19(2H,ddd,J=1.6,1.7,8.1 Hz), 8.66(1H,s),8.78(1H,dd,J=1.7,4.6 Hz), 9.08(1H,dd,J=1.1,1.6 Hz), 9.62(1H,brq,J=5.0Hz). IR (KBr) cm⁻¹: 3339,1679,1601,1535,1515,1412,1317,1253. Mass (m/z):469 (M⁺).

Example 82 Preparation of2-(2,4-Dichlorobenzyl)-6-(4-methoxy-phenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-(2,4-dichlorobenzyl)-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 97.4%.

Fine pale yellow needles (chloroform-hexane); Melting point:154.2-156.2° C.; ¹H-NMR (CDCl₃) δ: 3.01(3H,d,J=5.0 Hz), 3.86(3H,s),5.57(2H,s), 6.98(2H,d,J=8.9 Hz), 7.16(1H,d,J=8.3 Hz),7.22(1H,dd,J=2.0,8.3 Hz), 7.45(1H,d,J=2.0 Hz), 7.79(2H,d,J=8.9 Hz),8.72(1H,s), 9.54(1H,br). IR (KBr) cm⁻¹:3288,1683,1629,1610,1592,1474,1516,1411, 1255,1165,834. Mass (m/z): 421(M⁺), 419 (M⁺), 417 (M⁺).

Example 83 Preparation of6-(4-Methoxyphenyl)-4-methylcarbamoyl-2-(3-pyridylmethyl)-2H-pyridazin-3-one

Using4-methoxycarbonyl-6-(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 87.7%.

Slightly yellow needles (chloroform-hexane); Melting point: 153.8-154.3°C. (dec.); ¹H-NMR (CDCl₃) δ: 3.01(3H,d,J=5.0 Hz), 3.87(3H,s),5.47(2H,s), 7.00(2H,d,J=9.1 Hz), 7.25-7.32(1H,m), 7.78-7.85(3H,m),8.56-8.59(1H,m), 8.67(1H,s), 8.77-8.80(1H,m), 9.55(1H,br). IR (KBr)cm⁻¹: 3253,1679,1547,1518,1417,1316,1251,1028, 833,796. Mass (m/z): 350(M⁺).

Example 84 Preparation of2-Cinnamyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using 2-cinnamyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 100%.

Pale yellow prisms (chloroform-diethyl ether-hexane); Melting point:160.0-161.0° C.; ¹H-NMR (CDCl₃) δ: 3.02(3H,d,J=5.1 Hz), 3.86(3H,s),5.07(2H,dd,J=1.2,6.6 Hz), 6.43(1H,td,J=6.6,15.8 Hz), 6.73(1H,d,J=15.9Hz), 6.99(2H,d,J=8.8 Hz), 7.27(2H,d,J=8.6 Hz), 7.23-7.34(3H,m),7.40(2H,dd,J=1.2,8.1 Hz), 7.83(2H,d,J=9.0 Hz), 8.68(1H,s), 9.66(1H,brs).IR (KBr) cm⁻¹: 3245,1686,1611,1516,1024,835.

Example 85 Preparation of2-(4-Chlorocinnamyl)-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 43 were repeatedlikewise, whereby the title compound was obtained in a yield of 93.3%.

Pale yellow fine needles (chloroform-hexane); Melting point:184.2-185.4° C.; ¹H-NMR (CDCl₃) δ: 3.03(3H,d,J=4.6 Hz), 3.87(3H,s),5.06(2H,d,J=6.6 Hz), 6.40(1H,td,J=6.6,15.8 Hz), 6.67(1H,d,J=15.8 Hz),7.00(2H,d,J=8.6 Hz), 7.27(2H,d,J=8.6 Hz), 7.33(2H,d,J=8.6 Hz),7.84(2H,d,J=8.6 Hz), 8.69(1H,s), 9.63(1H,brd,J=4.6 Hz). IR (KBr) cm⁻¹:3246,1677,1550,1519,1491,1402,1260,1186, 1158, 1029,841. Mass (m/z): 411(M⁺), 409 (M⁺).

Example 86 Preparation of4-Carboxy-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a suspension of2-(4-chlorocinnamyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(1.35 g, 3.29 mmol) in methanol (50 ml), a 4N aqueous solution of sodiumhydroxide (20 ml) was added at room temperature, followed by stirring atthe same temperature for 30 minutes. The methanol was distilled offunder reduced pressure, and water (100 ml) was added to the residue. Themixture was acidified with hydrochloric acid under ice-water cooling,followed by extraction with chloroform. The organic layer was washedwith brine and then dried over anhydrous sodium sulfate. The solvent wasdistilled off, whereby the title compound (1.30 g, 99.7%) was obtainedas yellow crystals.

Melting point: 222.6-224.0° C. (dec.); ¹H-NMR (CDCl₃) δ: 3.88(3H,s),5.10(2H,d,J=6.8 Hz), 6.40(1H,td,J=6.8,15.6 Hz), 6.74(1H,d,J=15.6 Hz),7.01(2H,d,J=8.8 Hz), 7.34(2H,d,J=8.8 Hz), 7.81(2H,d,J=8.8 Hz),8.65(1H,s), 14.10(1H,brd). IR (KBr) cm⁻¹:1743,1630,1609,1561,1518,1475,1420,1252, 1029,900,837,814. Mass (m/z):398 (M⁺), 396 (M⁺).

Example 87 Preparation of2-(4-Chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a suspension of4-carboxy-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one(657 mg, 1.66 mmol) in benzene (15 ml), triethylamine (168 mg, 1.66mmol) and diphenylphosphorylazide (456 mg, 1.66 mmol) were added at roomtemperature. The mixture was stirred at the same temperature for 30minutes and then heated under reflux at 100° C. for 30 minutes. Ethanol(20 ml) was then added to the reaction mixture, followed by heatingunder reflux at 100° C. for 15 hours. The solvent was distilled offunder reduced pressure, and the residue was separated and purified bychromatography on a silica gel column [silica gel: 50 g, hexane/ethylacetate (3/1)]. Crystallization was conducted from chloroform-hexane,whereby the title compound (327 mg, 44.9%) was obtained as slightlyyellow fine needles.

Melting point: 171.2-172.1° C. ¹H-NMR (CDCl₃) δ: 1.34(3H,t,J=7.1 Hz),3.86(3H,s), 4.28(2H,q,J=7.1 Hz), 4.99(2H,dd,J=1.0,6.3 Hz),6.40(1H,td,J=6.3,15.9 Hz), 6.65(1H,td,J=1.0,15.9 Hz), 6.96(2H,d,J=8.8Hz), 7.26(2H,d,J=8.6 Hz), 7.31(2H,d,J=8.6 Hz), 7.78(2H,d,J=8.8 Hz),8.08(1H,brs), 8.26(1H,s). IR (KBr) cm⁻¹:3224,1727,1642,1606,1540,1518,1491,1256,1225,1177,830. Mass (m/z): 441(M⁺), 439 (M⁺).

Example 88

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-isopropoxycarbonylamino-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 87 were repeated likewisein isopropyl alcohol, whereby the title compound was obtained in a yieldof 41.4%.

Pale yellow fine needles (chloroform-hexane)

Melting point: 123.9-127.4° C. ¹H-NMR (CDCl3) δ: 1.33(6H,d,J=6.4 Hz),3.86(3H,s), 4.97-5.10(3H,m), 6.40(1H,td,J=6.4,15.9 Hz),6.64(1H,td,J=1.2,15.9 Hz), 6.96(2H,d,J=8.9 Hz), 7.29(2H,d,J=8.9 Hz),7.30(2H,d,J=8.9 Hz), 7.30(2H,d,J=8.9 Hz), 7.79(2H,d,J=8.9 Hz),8.03(1H,brs), 8.26(1H,s). IR (KBr) cm⁻¹:3370,3056,1732,1645,1613,1535,1518,1497,1256,1178,1111,832. Mass (m/z):455 (M⁺), 453 (M⁺).

Example 89

Preparation of4-n-butoxycarbonylamino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 87 were repeated likewisein n-butanol, whereby the title compound was obtained in a yield of37.3%.

Pale yellow needles (chloroform-hexane)

Melting point: 150.2-150.9° C. ¹H-NMR (CDCl₃) δ: 0.96(3H,t,J=7.4 Hz),1.35-1.50(2H,m), 1.63-1.75(2H,m), 3.86(3H,s), 4.23(2H,t,J=6.6 Hz),4.99(2H,dd,J=1.2,6.4 Hz), 6.40(1H,td,J=6.4,15.8 Hz),6.64(1H,td,J=1.2,15.8 Hz), 6.96(2H,d,J=8.9 Hz), 7.27(2H,d,J=8.9 Hz),7.30(2H,d,J=8.9 Hz), 7.78(2H,d,J=8.9 Hz), 8.08(1H,brs), 8.26(1H,s). IR(KBr) cm⁻¹: 3223,3031,1728,1641,1606,1541,1516,1491,1247,1220,1181. Mass(m/z): 469 (M⁺), 467 (M⁺).

Example 90

Preparation of4-benzyloxycarbonylamino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 87 were repeated likewisein benzyl alcohol, whereby the title compound was obtained in a yield of12.1%.

Pale yellow fine needles (chloroform-hexane)

Melting point: 190.5-191.7° C. ¹H-NMR (CDCl₃) δ: 3.85(3H,s),4.98(2H,dd,J=1.0,6.4 Hz), 5.25(2H,s), 6.39(1H,td,J=6.4,15.9 Hz),6.63(1H,td,J=1.0,15.9 Hz), 6.96(2H,d,J=9.0 Hz), 7.29(2H,d,J=8.8 Hz),7.30(2H,d,J=8.8 Hz), 7.32-7.44(5H,m), 7.77(2H,d,J=9.0 Hz), 8.17(1H,brs),8.26(1H,s). IR (KBr) cm⁻¹:3231,3034,1729,1640,1607,1540,1516,1252,1223,1210. Mass (m/z): 503 (M⁺),501 (M⁺).

Example 91

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-[4-(methylthio)benzyloxycarbonylamino]-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 87 were repeated likewisein 4-(methylthio)benzyl alcohol, whereby the title compound was obtainedin a yield of 46.0%.

Slightly yellow fine needles (chloroform-hexane)

Melting point: 187.6-188.7° C. ¹H-NMR (CDCl3) δ: 2.49(3H,s), 3.85(3H,s),4.98(2H,dd,J=1.2,6.4 Hz), 5.20(2H,s), 6.39(1H,td,J=6.4,15.9 Hz),6.42(1H,td,J=1.2,15.9 Hz), 6.96(2H,d,J=8.9 Hz), 7.23-7.36(8H,m),7.77(2H,d,J=8.9 Hz), 8.15(1H,brs), 8.24(1H,s). IR (KBr) cm⁻¹:3224,3028,1729,1640,1605,1541,1518,1501,1491,1252,1176. Mass (m/z): 549(M⁺), 547 (M⁺).

Example 92

Preparation of4-carboxy-6-(4-methoxyphenyl)-2-(3-methyl-2-butenyl)-2H-pyridazin-3-one

Using6-(4-methoxyphenyl)-4-ethoxycarbonyl-2-(3-methyl-2-butenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 93.1%.

Pale yellow needles (chloroform-hexane)

Melting point: 153.5-156.6° C. ¹H-NMR (CDCl₃) δ: 1.78(3H,s), 1.88(3H,s),3.87(3H,s), 4.94(2H,d,J=6.8 Hz), 5.38-5.54(1H,m), 7.01(2H,d,J=8.8 Hz),7.80(2H,d,J=8.8 Hz), 8.62(1H,s), 14.27(1H,br). IR (KBr) cm⁻¹:1740,1653,1629,1609,1517,1477,1420,1252,900. Mass (m/z): 314 (M⁺).

Example 93

Preparation of4-ethoxycarbonylamino-6-(4-methoxy-phenyl)-2-(3-methyl-2-butenyl)-2H-pyridazin-3-one

Using4-carboxy-6-(4-methoxyphenyl)-2-(3-methyl-2-butenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 25.9%.

Pale yellow needles (chloroform-hexane)

Melting point: 130.2-131.2° C. ¹H-NMR (CDCl₃) δ: 1.33(3H,t,J=7.1 Hz),1.75(3H,s), 1.87(3H,s), 3.86(3H,s), 4.27(2H,q,J=7.1 Hz), 4.84(2H,d,J=7.1Hz), 5.41-5.50(1H,m), 6.96(2H,d,J=8.8 Hz), 7.78(2H,d,J=8.8 Hz),8.09(1H,br), 8.23(1H,s). IR (KBr) cm⁻¹:3216,1722,1644,1605,1539,1518,1255,1225,1176,1027,832. Mass (m/z): 357(M⁺).

Example 94

Preparation of4-carboxy-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 99.7%.

Yellow crystals

Melting point: 153.9-154.7° C. ¹H-NMR (CDCl₃) δ: 0.50-0.66(4H,m),1.41-1.51(1H,m), 3.88(3H,s), 4.23(2H,d,J=7.3 Hz), 7.02(2H,d,J=8.9 Hz),7.81(2H,d,J=8.9 Hz), 8.64(1H,s), 14.31(1H,br). IR (KBr) cm⁻¹:1743,1630,1608,1558,1515,1482,1461,1418.

Example 95

Preparation of2-cyclopropylmethyl-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4-carboxy-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 44.2%.

Colorless needles (chloroform-hexane)

Melting point: 119.1-119.6° C. ¹H-NMR (CDCl₃) δ: 0.45-0.60(4H,m),1.32-1.45(4H,m), 3.86(3H,s), 4.11(2H,d,J=7.3 Hz), 4.28(2H,q,J=7.1 Hz),6.96(2H,d,J=8.9 Hz), 7.79(2H,d,J=8.9 Hz), 8.10(1H,br), 8.25(1H,s). IR(KBr) cm⁻¹: 3320,1722,1636,1606,1541,1515,1250,1178,1031,1021,887,836.Mass (m/z): 343 (M⁺).

Example 96

Preparation of2-benzyl-4-carboxy-6-(4-methoxy-phenyl)-2H-pyridazin-3-one

Using 2-benzyl-4-ethoxycarbonyl-6-(4-methoxy-phenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 94.8%.

Yellow crystals

¹H-NMR (CDCl3) δ: 3.88(3H,s), 5.50(2H,s), 7.01(2H,d,J=8.8 Hz),7.30-7.55(5H,m), 7.81(2H,d,J=8.8 Hz), 8.62(1H,s), 14.14(1H,br). IR (KBr)cm⁻¹: 1750,1633,1607,1516,1472,1457,1419,1250,1026,898,838. Mass (m/z):336 (M⁺).

Example 97

Preparation of2-benzyl-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 2-benzyl-4-carboxy-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 87 were repeated likewise,whereby the title compound was obtained in a yield of 11.2%.

Pale yellow needles (chloroform-diethyl ether)

Melting point: 152.1-162.5° C. ¹H-NMR (CDCl3) δ: 1.33(3H,t,J=7.1 Hz),3.86(3H,s), 4.25(2H,q,J=7.1 Hz), 5.40(2H,s), 6.96(2H,d,J=8.9 Hz),7.27-7.38(3H,m), 7.45-7.50(2H,m), 7.78(2H,d,J=8.9 Hz), 8.07(1H,brs),8.24(1H,s). IR (KBr) cm⁻¹:3225,1728,1641,1606,1540,1516,1256,1226,1180,1171,829. Mass (m/z): 379(M⁺).

Example 98

Preparation of4-carboxy-6-(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using4-methoxycarbonyl-6-(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 85.8%.

Pale yellow needles (chloroform-hexane)

Melting point: 121.0-122.1° C. ¹H-NMR (CDCl₃) δ: 2.23-2.36(2H,m),2.77(2H,t,J=7.3 Hz), 3.88(3H,s), 4.41(2H,t,J=7.3 Hz), 7.01(2H,d,J=8.8Hz), 7.14-7.30(5H,m), 7.79(2H,d,J=8.8 Hz), 8.57(1H,s), 14.21(1H,br). IR(KBr) cm⁻¹: 1740,1632,1609,1515,1474,1451,1417,1249,1187,837.

Example 99

Preparation of4-ethoxycarbonylamino-6-(4-methoxy-phenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using4-carboxy-6-(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one as astarting material, the procedures of Example 87 were repeated likewise,whereby the title compound was obtained in a yield of 41.1%.

Colorless needles (chloroform-diethyl ether-hexane)

Melting point: 100.9-101.3° C. ¹H-NMR (CDCl₃) δ: 1.35(3H,t,J=7.76 Hz),2.16-2.28(2H,m), 2.73(2H,t,J=7.7 Hz), 3.86(3H,s), 4.28(2H,q,J=7.1 Hz),4.30(2H,t,J=7.6 Hz),6.96(2H,d,J=9.0 Hz), 7.14-7.31(5H,m),7.77(2H,d,J=9.0 Hz), 8.08(1H,brs), 8.22(1H,s). IR (KBr) cm⁻¹:3223,1725,1641,1608,1547,1517,1225,1200,1175.

Example 100

Preparation of4-benzyloxycarbonylamino-6-(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3-one

Using4-carboxy-6-(4-methoxyphenyl)-2-(3-phenyl-propyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 90 were repeatedlikewise, whereby the title compound was obtained in a yield of 52.8%.

Colorless needles (chloroform-hexane)

Melting point: 117.6-118.1° C. (dec.) ¹H-NMR (CDCl₃) δ: 2.15-2.27(2H,m),2.72(2H,t,J=7.1 Hz), 3.86(3H,s), 4.29(2H,t,J=7.1 Hz), 5.23(2H,s),6.36(2H,d,J=8.9 Hz), 7.13-7.30(5H,m), 7.32-7.44(5H,m), 7.76(2H,d,J=8.9Hz), 8.16(1H,brs), 8.22(1H,s). IR (KBr) cm⁻¹:3221,1733,1640,1604,1539,1516,1500,1252,1220,1175.

Example 101

Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(3,4-dimethoxyphenyl)-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-6-(3,4-dimethoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 99.1%.

Yellow fine needles (chloroform-hexane)

Melting point: 229.5-230.9° C. (dec.) ¹H-NMR (CDCl₃) δ: 3.95(6H,s),5.11(2H,dd,J=1.0,6.8 Hz), 6.40(1H,td,J=6.8,16.1 Hz),6.75(1H,td,J=1.0,16.1 Hz), 6.97(1H,d,J=8.8 Hz), 7.33(2H,d,J=8.8 Hz),7.39-7.45(2H,m), 8.67(1H,s), 14.09(1H,brs). IR (KBr) cm⁻¹:1753,1635,1570,1520,1471,1460,1238. Mass (m/z): 428 (M⁺), 426 (M⁺).

Example 102

Preparation of2-(4-chlorocinnamyl)-6-(3,4-dimethoxyphenyl)-4-ethoxycarbonylamino-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl)-6-(3,4-dimethoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 43.6%.

Slightly yellow needles (chloroform-hexane)

Melting point: 183.8-184.8° C. ¹H-NMR (CDCl₃) δ: 1.35(3H,t,J=7.3 Hz),3.93(3H,s), 3.94(3H,s), 4.29(2H,q,J=7.3 Hz), 5.01(2H,dd,J=1.0,6.6 Hz),6.41(1H,td,J=6.3,15.8 Hz), 6.65(1H,dt,J=15.8,1.0 Hz), 6.92(1H,d,J=8.2Hz), 7.26(2H,d,J=8.6 Hz), 7.31(2H,d,J=8.6 Hz), 7.37(1H,dd,J=2.2,8.2 Hz),7.42(1H,d,J=2.0 Hz), 8.09(1H,br), 8.27(1H,s). IR (KBr) cm⁻¹:3232,3023,1725,1636,1607,1544,1519,1491,1423,1262,1223,1151,1022. Mass(m/z): 471 (M⁺), 469 (M⁺).

Example 103

Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 96.5%.

Pale yellow fine needles (chloroform-hexane)

Melting point: 215.8-219.2° C. ¹H-NMR (CDCl₃) δ: 3.97(3H,s),5.10(2H,dd,J=1.5,6.8 Hz), 6.39(1H,td,J=6.8,16.1 Hz),6.75(1H,td,J=1.5,16.1 Hz), 7.03-7.10(1H,m), 7.30(2H,d,J=9.0 Hz),7.33(2H,d,J=9.0 Hz), 7.54-7.59(1H,m), 7.66-7.72(1H,m), 8.61(1H,s),13.99(1H,br). IR (KBr) cm⁻¹: 1745,1628,1523,1481,1437,1271. Mass (m/z):416 (M⁺), 414 (M⁺).

Example 104

Preparation of2-(4-chlorocinnamyl)-4-ethoxy-carbonylamino-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 29.4%.

Slightly yellow fine needles (chloroform-hexane)

Melting point: 186.7-187.5° C. ¹H-NMR (CDCl₃) δ: 1.35(3H,t,J=7.1 Hz),3.94(3H,s), 4.29(2H,q,J=7.1 Hz), 4.99(2H,dd,J=1.2,6.6 Hz),6.39(1H,td,J=6.6,16.1 Hz), 6.65(1H,td,J=1.2,16.1 Hz), 6.97-7.04(1H,m),7.27(2H,d,J=8.8 Hz), 7.30(2H,d,J=8.8 Hz), 7.51-7.56(1H,m),7.62-7.68(1H,m), 8.08(1H,brs), 8.24(1H,s). IR (KBr) cm⁻¹:3217,1728,1644,1610,1544,1520. Mass (m/z): 459 (M⁺), 457 (M⁺).

Example 105

Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(3-chloro-4-methoxyphenyl)-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-6-(3-chloro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 95.1%.

Pale yellow crystalline powder (chloroform-hexane) ¹H-NMR (CDCl₃) δ:3.98(3H,s), 5.11(2H,dd,J=1.0,6.8 Hz), 6.39(1H,td,J=6.8,15.6 Hz),6.76(1H,td,J=1.0,15.6 Hz), 7.03(1H,d,J=8.6 Hz), 7.30(2H,d,J=8.8 Hz),7.33(2H,d,J=8.8 Hz), 7.71(1H,dd,J=2.1,8.6 Hz), 7.96(1H,d,J=2.1 Hz),8.63(1H,s), 13.99(1H,br). IR (KBr) cm⁻¹:1748,1628,1508,1481,1407,1292,1260. Mass (m/z): 432 (M⁺), 430 (M⁺).

Example 106

Preparation of2-(4-chlorocinnamyl)-6-(3-chloro-4-methoxyphenyl)-4-ethoxycarbonylamino-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl)-6-(3-chloro-4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 44.9%.

Colorless fine needles (chloroform-hexane)

Melting point: 183.0-183.8° C. ¹H-NMR (CDCl₃) δ: 1.35(3H,t,J=7.1Hz),3.95(3H,s), 4.29(2H,q,J=7.1 Hz), 4.99(2H,dd,J=1.0,6.6 Hz),6.40(1H,td,J=6.6,15.8 Hz), 6.66(1H,dt,J=15.8,1.0 Hz), 6.97(1H,d,J=8.6Hz), 7.27(2H,d,J=8.7 Hz), 7.31(2H,d,J=8.7 Hz), 7.69(1H,dd,J=2.3,8.6 Hz),7.91(1H,d,J=2.3 Hz), 8.09(1H,brs),8.24(1H,s). IR (KBr) cm⁻¹:3235,1724,1641,1606,1540,1508,1264,1229. Mass (m/z): 475 (M⁺), 473 (M⁺).

Example 107

Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-4-methoxycarbonyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 77.1%.

Yellow prisms (chloroform-hexane)

Melting point: 176.0-177.6° C. (dec.) ¹H-NMR (CDCl₃) δ: 2.54(3H,s),5.11(2H,d,J=6.8 Hz), 6.39(1H,td,J=6.8,15.9 Hz), 6.74(1H,d,J=15.9 Hz),7.25-7.37(6H,m), 7.78(2H,d,J=8.8 Hz), 8.66(1H,s), 14.01(1H,br). IR (KBr)cm⁻¹: 1749,1655,1630,1594,1567,1492,1474,1403. Mass (m/z): 414 (M⁺), 412(M⁺).

Example 108

Preparation of2-(4-chlorocinnamyl)-4-ethoxy-carbonylamino-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

Using4-carboxy-2-(4-chlorocinnamyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 13.6%.

Pale yellow fine needles (chloroform-hexane)

Melting point: 158.3-162.1° C. ¹H-NMR (CDCl₃) δ: 1.35(3H,t,J=7.1 Hz),2.52(3H,s), 4.29(2H,q,J=7.1 Hz), 5.00(2H,dd,J=1.1,6.5 Hz),6.40(1H,td,J=6.5,15.9 Hz), 6.65(1H,td,J=1.1,15.9 Hz), 7.27(2H,d,J=8.8Hz), 7.30(2H,d,J=8.7 Hz), 7.30(2H,d,J=8.8 Hz), 7.76(2H,d,J=8.7 Hz),8.13(1H,br), 8.27(1H,s). IR (KBr) cm⁻¹:3220,1728,1641,1606,1538,1501,1491. Mass (m/z): 457 (M⁺), 455 (M⁺).

Example 109

Preparation of4-carboxy-2-(2,4-difluorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-(2,4-difluorocinnamyl)-4-methoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 86 were repeatedlikewise, whereby the title compound was obtained in a yield of 93.1%.

Slightly yellow fine needles (chloroform-hexane)

Melting point: 200.3-201.3° C. ¹H-NMR (CDCl₃) δ: 3.88(3H,s),5.11(2H,dd,J=1.2,6.8 Hz), 6.45(1H,td,J=6.8,16.1 Hz), 6.73-6.92(3H,m),7.01(2H,d,J=8.8 Hz), 7.37-7.48(1H,m), 7.82(2H,d,J=8.8 Hz), 8.66(1H,s),14.09(1H,brs). IR (KBr) cm⁻¹:3065,1741,1632,1608,1504,1474,1419,1252,967. Mass (m/z): 398 (M⁺).

Example 110

Preparation of2-(2,4-difluorocinnamyl)-4-ethoxy-carbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4-carboxy-2-(2,4-difluorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 87 were repeatedlikewise, whereby the title compound was obtained in a yield of 30.0%.

Pale yellow needles (chloroform-hexane)

Melting point: 128.3-128.9° C. ¹H-NMR (CDCl₃) δ: 3.15(3H,t,J=7.1 Hz),3.86(3H,s), 4.28(2H,q,J=7.1 Hz), 5.01(2H,dd,J=1.2,6.6 Hz),6.44(1H,td,J=6.6,16.1 Hz), 6.73-6.86(3H,m), 6.96(2H,d,J=8.8 Hz),7.36-7.46(1H,m), 7.79(2H,d,J=8.8 Hz), 8.08(1H,brs), 8.26(1H,s). IR (KBr)cm⁻¹: 3221,3073,1728,1641,1605,1541,1519,1502,1256,1224,1176. Mass(m/z): 398(M⁺).

Example 111

Preparation of4-amino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a suspension of2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-(4-methoxyphenyl)-2H-pyridazin-3-one(335 mg, 0.76 mmol) in methanol (40 ml), a 4N aqueous solution of sodiumhydroxide (20 ml) was added, followed by stirring at 70° C. for 30minutes. The methanol was distilled off. Water (100 ml) was added to theresidue, followed by extraction with chloroform. The organic layer waswashed with brine and then dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue was separated and purified bychromatography on a silica gel column (silica gel: 10 g, chloroform).Crystallization was conducted from chloroform-hexane, whereby the titlecompound (266 mg, 95.0%) was obtained as colorless fine needles.

Melting point: 142.7-143.2° C. ¹H-NMR (CDCl₃) δ: 3.84(3H,s),4.93-5.01(4H,m), 6.43(1H,td,J=6.4,15.9 Hz), 6.64(1H,td,J=1.0,15.9 Hz),6.69(1H,s), 6.95(2H,d,J=8.9 Hz), 7.25(2H,d,J=8.6 Hz), 7.31(2H,d,J=8.6Hz), 7.69(2H,d,J=8.9 Hz). IR (KBr) cm⁻¹:3435,3325,3038,1646,1612,1597,1521,1491,1252,1238,833. Mass (m/z): 369(M⁺), 367 (M⁺).

Example 112

Preparation of2-(4-chlorocinnamyl)-4-formylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of4-amino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one (40mg, 0.11 mmol) in benzene (2 ml), triethylamine (151 mg, 1.49 mmol) anda formic acid-acetic acid (1:1) mixed solution (0.5 ml) were added,followed by stirring at room temperature for 16 hours. The reactionmixture was extracted with chloroform. The extract was washedsuccessively with a saturated solution of sodium hydrogencarbonate andbrine, and was then dried over anhydrous sodium sulfate. The solvent wasdistilled off and the residue was crystallized from chloroform-hexane,whereby the title compound (41 mg, 95.2%) was obtained as colorlessneedles.

Melting point: 213.0-213.8° C. ¹H-NMR (CDCl₃) δ: 3.86(3H,s),5.00(2H,dd,J=1.0,6.5 Hz), 6.40(1H,td,J=6.5,15.9 Hz),6.66(1H,td,J=1.0,15.9 Hz), 6.97(2H,d,J=9.0 Hz), 7.26(2H,d,J=8.8 Hz),7.32(2H,d,J=8.8 Hz), 7.79(2H,d,J=9.0 Hz), 8.59(1H,s), 8.64(1H,s),8.79(1H,br). IR (KBr) cm⁻¹:3277,1702,1634,1601,1549,1518,1491,1418,1245,1138,1033,812. Mass (m/z):397 (M⁺), 395 (M⁺).

Example 113

Preparation of4-acetylamino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Acetic anhydride (0.5 m!) was added to4-amino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one (40mg, 0.11 mmol), followed by heating under stirring at 70° C. for 12hours. A saturated aqueous solution of sodium hydrogencarbonate wasadded to the reaction mixture. Subsequent to stirring at roomtemperature for 1 hour, the mixture was extracted with ethyl acetate.The organic layer was washed with brine and then dried over anhydroussodium sulfate. The solvent was distilled off, and the residue wasseparated and purified by silica gel preparative chromatography[developer: hexane/ethyl acetate (1/1)]. Crystallization was conductedfrom chloroform-hexane, whereby the title compound (31 mg, 70.0%) wasobtained as slightly brown needles.

Melting point: 158.7-161.9° C. ¹H-NMR (CDCl₃) δ: 2.27(3H,s), 3.86(3H,s),5.00(2H,dd,J=1.2,6.4 Hz), 6.39(1H,td,J=6.5,15.9 Hz),6.65(1H,td,J=1.2,15.9 Hz), 6.97(2H,d,J=9.0 Hz), 7.27(2H,d,J=8.9 Hz),7.30(2H,d,J=8.9 Hz), 7.79(2H,d,J=9.0 Hz), 8.58(1H,s), 8.61(1H,brs). IR(KBr) cm⁻¹: 3274,3002,1701,1634,1603,1537,1516,1491,1405,1252,1180,1070.Mass (m/z): 411 (M⁺), 409 (M⁺).

Example 114

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxy-phenyl)-4-propionylamino-2H-pyridazin-3-one

4-Amino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one andpropionic anhydride were processed as in Example 113, whereby the titlecompound was obtained in a yield of 84.6%.

Colorless needles (chloroform-hexane)

Melting point: 147.7-148.6° C. ¹H-NMR (CDCl₃) δ: 1.26(3H,t,J=7.6 Hz),2.51(2H,q,J=7.6 Hz), 3.86(3H,s), 5.00(2H,dd,J=1.2,6.4 Hz),6.40(1H,td,J=6.4,15.9 Hz), 6.65(1H,td,J=1.2,15.9 Hz), 7.27(2H,d,J=8.8Hz), 7.30(2H,d,J=8.8 Hz), 7.79(2H,d,J=9.0 Hz), 8.61(1H,brs), 8.62(1H,s).IR (KBr) cm⁻¹: 3270,3046,1633,1599,1534,1516,1492,1255,1173,833,772.Mass (m/z): 425 (M⁺), 423 (M⁺).

Example 115

Preparation of4-n-butyrylamino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

4-Amino-2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one andbutyric anhydride were processed as in Example 113, whereby the titlecompound was obtained in a yield of 88.2%.

Colorless needles (chloroform-hexane)

Melting point: 152.1-152.7° C. ¹H-NMR (CDCl₃) δ: 1.04(3H,t,J=7.5 Hz),1.70-1.85(2H,m), 2.45(2H,t,J=7.3 Hz), 3.86(3H,s), 5.00(2H,dd,J=1.2,6.4Hz), 6.41(1H,td,J=6.4,15.9 Hz), 6.64(1H,td,J=1.2,15.9 Hz),6.96(2H,d,J=8.9 Hz), 7.27(2H,d,J=8.8 Hz), 7.30(2H,d,J=8.8 Hz),7.79(2H,d,J=8.9 Hz), 8.60(1H,brs), 8.62(1H,s). IR (KBr) cm⁻¹:3271,3051,3034,1632,1598,1532,1517,1500,1258,1172. Mass (m/z): 439 (M⁺),437 (M⁺).

Example 116

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxy-phenyl)-4-(N-methylethoxycarbonylamino)-2H-pyridazin-3-one

In N,N-dimethylformamide,2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one(100 mg) was stirred at 80° C. for 1 hour in the presence of methyliodide and potassium carbonate. The procedures of Example 1 were thenrepeated likewise, whereby the title compound (92 mg, 89.2%) wasobtained.

Slightly yellow fine needles (chloroform-hexane)

Melting point: 130.8-131.5° C. ¹H-NMR (CDCl₃) δ: 1.27(3H,t,J=7.1 Hz),3.30(3H,s), 3.86(3H,s), 4.22(2H,q,J=7.1 Hz), 5.00(2H,dd,J=1.0,6.3 Hz),6.42(1H,td,J=6.6,15.9 Hz), 6.67(1H,td,J=1.0,15.9 Hz), 6.97(2H,d,J=9.0Hz), 7.27(2H,d,J=8.7 Hz), 7.31(2H,d,J=8.7 Hz), 7.63(1H,s),7.71(2H,d,J=9.0 Hz). IR (KBr) cm⁻¹:1706,1655,1611,1520,1316,1307,1252,1176. Mass (m/z): 455 (M⁺), 453 (M⁺).

Example 117

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-methylamino-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-(N-methylethoxycarbonylamino)-2H-pyridazin-3-one(68 mg) as a starting material, the procedures of Example 111 wererepeated likewise (stirred at 70° C. for 1 hour), whereby the titlecompound (49 mg, 93.9%) was obtained.

Colorless needles (chloroform-hexane)

Melting point: 148.4-149.2° C. ¹H-NMR (CDCl₃) δ: 2.96(3H,d,J=5.1 Hz),3.85(3H,s), 4.96(2H,dd,J=1.2,6.4 Hz), 5.77(2H,brq,J=5.1 Hz), 6.33(1H,s),6.42(1H, td,J=6.4,15.9 Hz), 6.62(1H,td,J=1.2,15.9 Hz), 6.96(2H,d,J=9.0Hz), 7.25(2H,d,J=8.9 Hz), 7.30(2H,d,J=8.9 Hz), 7.74(2H,d,J=9.0 Hz). IR(KBr) cm⁻¹: 3318,1630,1606,1519,1432,1240. Mass (m/z): 383 (M⁺), 381(M⁺).

Example 118

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-[N-(3-phenylpropyl)ethoxycarbonylamino]-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one(70 mg) and 3-phenylpropyl bromide as starting materials, the proceduresof Example 116 were repeated likewise, whereby the title compound (61mg, 68.7%) was obtained.

Colorless fine needles (chloroform-diethyl ether-hexane)

Melting point: 113.5-114.2° C. ¹H-NMR (CDCl₃) δ: 1.22(3H,t,J=7.1 Hz),1.85-1.98(2H,m), 2.65(2H,t,J=7.7 Hz), 3.79(2H,t,J=7.4 Hz), 3.86(3H,s),4.19(2H,q,J=7.1 Hz), 4.99(2H,dd,J=1.0,6.3 Hz), 6.42(1H,td,J=6.6,15.9Hz), 6.65(1H,td,J=1.0,15.9 Hz), 6.97(2H,d,J=8.8 Hz), 7.27(2H,d,J=8.9Hz), 7.10-7.33(9H,m), 7.48(1H,s), 7.68(2H,d,J=8.8 Hz). IR (KBr) cm⁻¹:1678,1657,1616,1522,1305,1252,1183,1166. Mass (m/z): 559 (M⁺), 557 (M⁺).

Example 119

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-(3-phenylpropyl)amino)-2H-pyridazin-3-one

Using2-(4-chlorocinnamyl)-6-(4-methoxyphenyl)-4-[N-(3-phenylpropyl)ethoxycarbonylamino]-2H-pyridazin-3-one(31 mg) as a starting material, the procedures of Example 111 wererepeated likewise, whereby the title compound (26 mg, 96.3%) wasobtained.

Colorless fine needles (chloroform-hexane)

Melting point: 161.2-162.6° C. ¹H-NMR (CDCl₃) δ: 1.96-2.09(2H, m),2.76(2H,t,J=7.4 Hz), 3.17-3.26(2H,m), 3.85(3H,s), 4.96(2H,dd,J=1.2,6.4Hz), 5.79(1H,brt,J=5.5 Hz), 6.25(1H,s), 6.43(1H,td,J=6.4,15.9 Hz),6.63(1H,td,J=1.2,15.9 Hz), 6.95(2H,d,J=8.9 Hz), 7.17-7.34(9H,m),7.68(2H,d,J=8.9 Hz). IR (KBr) cm ⁻¹: 3315,1630,1602,1519,1258,1177,821.Mass (m/z): 487 (M⁺), 485 (M⁺).

Example 120

Preparation of2-(4-chlorocinnamyl)-6-(4-methoxy-phenyl)-4-[N-(2-pyridylmethyl)ethoxycarbonylamino]-2H-pyridazin-3-one

2-(4-Chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one(70 mg) and 2-pyridylmethyl bromide were processed as in Example 116(stirred at 70° C. for 4 hours), whereby the title compound (82 mg,97.0%) was obtained.

Pale brown oil

¹H-NMR (CDCl₃) δ: 1.18(3H,t,J=7.1 Hz), 3.85(3H,s), 4.20(2H,q,J=7.1 Hz),4.98(2H,dd,J=1.0,6.3 Hz), 5.05(2H,s), 6.40(1H,td,J=6.6,15.9 Hz),6.63(1H,td,J=1.0,15.9 Hz), 6.95(2H,d,J=8.8 Hz), 7.11-7.17(1H,m),7.27(2H,d,J=9.0 Hz), 7.29(2H,d,J=9.0 Hz), 7.40-7.45(1H,m),7.59-7.64(1H,m), 7.67(2H,d,J=8.8 Hz), 7.78(1H,s), 8.49-8.53(1H,m). IR(film) cm⁻¹: 1716,1660,1652,1610,1519,1305,1252,1209,1169. Mass (m/z):532 (M⁺), 530 (M⁺).

In a manner known per se in the art, the monochloride of the titlecompound was obtained in a yield of 74.2%.

Pale brown amorphous

Melting point: 90° C. (softened) ¹H-NMR (CDCl3) δ: 1.16(3H,t,J=7.1 Hz),3.85(3H,s), 4.17(2H,q,J=7.1 Hz), 5.05(2H,dd,J=1.0,6.4 Hz), 5.09(2H,s),6.48(1H,td,J=6.4,15.9 Hz), 6.69(1H,td,J=1.0,15.9 Hz), 7.03(2H,d,J=8.8Hz), 7.30(2H,d,J=8.5 Hz), 7.40(2H,d,J=8.5 Hz), 7.72-7.79(1H,m),7.83(2H,d,J=8.8 Hz), 7.97-8.03(1H,m), 8.16(1H,s), 8.27-8.36(1H,m),8.69-8.74(1H,m). IR (KBr) cm⁻¹: 1717,1652,1570,1519,1305,1251,1225,1169.

Example 121

Preparation of 4-amino-2-benzyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-benzyl-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one asa starting material, the procedures of Example 111 were repeatedlikewise, whereby the title compound was obtained in a yield of 57.4%.

Slightly brown prisms (chloroform-hexane)

Melting point: 115.1-115.6° C. ¹H-NMR (CDCl₃) δ: 3.85(3H,s),4.94(2H,br), 5.39(2H,s), 6.95(2H,d,J=8.8 Hz), 7.24-7.37(3H,m),7.47-7.52(2H,m), 7.69(2H,d,J=8.8 Hz). IR (KBr) cm⁻¹:3419,3322,3286,3259,1644,1600,1519,1251,1184,1021,839. Mass (m/z): 307(M⁺).

Example 122

Preparation of2-benzyl-4-methanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

(1) Preparation of2-benzyl-4-dimethanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of 4-amino-2-benzyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(60 mg, 0.20 mmol) and triethylamine (80 mg, 0.79 mmol) in toluene (1ml), methanesulfonyl chloride (70 mg, 0.61 mmol) was added, followed byheating under stirring at 40° C. for 1 hour. Chloroform was added to thereaction mixture. The organic layer was washed with water and brine, andwas then dried over anhydrous sodium sulfate. The solvent was distilledoff under reduced pressure and the residue was separated and purified bysilica gel preparative chromatography [developer: hexane/ethyl acetate(1/1)], whereby the title compound (76 mg, 90.4%) was obtained.

¹H-NMR (CDCl₃) δ: 3.55(6H,s), 3.86(3H,s), 5.43(2H,s), 6.70(2H,d,J=9.2Hz), 7.27-7.37(3H,m), 7.42-7.46(2H,m), 7.65-7.70(3H,m).

(2) Preparation of2-benzyl-4-methanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of2-benzyl-4-dimethanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one(36 mg, 0.08 mmol) in methanol (1 ml), a 4N aqueous solution of sodiumhydroxide (1 ml) was added, followed by stirring at room temperature for2 hours. The reaction mixture was acidified with hydrochloric acid underice cooling, added with water (30 ml), and then extracted withchloroform (20 ml×2). The organic layer was washed with brine and thendried over anhydrous sodium sulfate. The solvent was distilled off andthe residue (31 mg) was crystallized from chloroform-hexane, whereby thetitle compound (26 mg, 86.9%) was obtained as slightly brown needles.

Melting point: 195.0-195.5° C. ¹H-NMR (CDCl₃) δ: 3.13(3H,s), 3.86(3H,s),5.40(2H,s), 6.98(2H,d,J=8.8 Hz), 7.30-7.39(3H,m), 7.47-7.51(2H,m),7.75(2H,d,J=8.8 Hz), 8.02(1H,br). IR (KBr) cm⁻¹:3151,1634,1599,1440,1250,1154,1021,835,770,753,700. Mass (m/z): 385(M⁺).

Example 123

Preparation of2-benzyl-4-(3-isopropylureido)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

To a solution of 4-amino-2-benzyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one(50 mg, 0.16 mmol) in benzene (2 ml), isopropyl isocyanate (0.1 ml, 1.02mmol) was added, followed by stirring at 60° C. for 17 hours. Thesolvent was distilled off, and the residue was separated and purified bysilica gel preparative chromatography [developer: chloroform/methanol(15/1)]. The crude crystals (63 mg) were recrystallized fromchloroform-hexane, whereby the title compound (56 mg, 87.7%) wasobtained as colorless needles.

Melting point: 200.2-201.0° C. ¹H-NMR (CDCl₃) δ: 1.15(3H,s), 1.18(3H,s),3.85(3H,s), 3.92-4.07(1H,m), 5.38-5.52(3H,m), 6.93(2H,d,J=8.9 Hz),7.25-7.45(5H,m), 7.79(2H,d,J=8.9 Hz), 8.31(1H,brs), 8.47(1H,s). IR (KBr)cm⁻¹: 3370,3283,1698,1624,1592,1517,1255,1175,1032,830,701. Mass (m/z):392 (M⁺).

Example 124

Preparation of4-amino-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 111 were repeatedlikewise (stirred at 60° C. for 40 minutes), whereby the title compound(82 mg, 97.0%) was obtained.

Colorless needles (chloroform-hexane)

Melting point: 110.8-111.3° C. ¹H-NMR (CDCl₃) δ: 0.44-0.59(4H,m),1.35-1.52(1H,m), 3.85(3H,s), 4.09(2H,d,J=7.3 Hz), 4.95(2H,br),6.68(1H,s), 6.95(2H,d,J=8.9 Hz), 7.70(2H,d,J=8.9 Hz). IR (KBr) cm⁻¹:3455,3300,3261,3206,1641,1601,1575,1520,1420,1246,1239,1025,835. Mass(m/z): 271 (M⁺).

Example 125

Preparation of2-cyclopropylmethyl-4-(3-isopropylureido)-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using 4-amino-2-cyclopropylmethyl-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Example 123 were repeatedlikewise, whereby the title compound was obtained in a yield of 77.0%.

Colorless needles (chloroform-hexane)

Melting point: 195.8-197.0° C. ¹H-NMR (CDCl₃) δ: 0.45-0.62(4H,m),1.24(3H,s), 1.27(3H,s), 1.34-1.51(1H,m), 3.85(3H,s), 4.00-4.15(3H,m),5.85(1H,brd,J=7.9 Hz), 6.95(2H,d,J=8.9 Hz), 7.81(2H,d,J=8.9 Hz),8.53(1H,s), 8.55(1H,brs). IR (KBr) cm⁻¹:3324,1694,1622,1611,1591,1538,1516,1253,1175,1033,836. Mass (m/z): 356(M⁺).

Example 126

Preparation of2-cyclopropylmethyl-4-methanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

(1) Preparation of2-cyclopropylmethyl-4-dimethanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using4-amino-2-cyclopropylmethyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one as astarting material, the procedures of Examples 122-(1) were repeatedlikewise, whereby the title compound was obtained in a yield of 90.1%.

¹H-NMR (CDCl₃) δ: 0.43-0.63(4H,m), 1.33-1.49(1H,m), 3.57(6H,s),3.87(3H,s), 4.13(2H,d,J=7.3 Hz), 6.99(2H,d,J=8.6 Hz), 7.71(2H,d,J=8.6Hz), 7.72(1H,s).

(2) Preparation of2-cyclopropylmethyl-4-methanesulfonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one

Using2-cyclopropylmethyl-4-dimethanesulfonyl-amino-6-(4-methoxyphenyl)-2H-pyridazin-3-oneas a starting material, the procedures of Examples 122-(2) were repeatedlikewise, whereby the title compound was obtained in a yield of 81.0%.

Colorless needles (chloroform-hexane)

Melting point: 203.3-203.9° C. ¹H-NMR (CDCl₃) δ: 0.45-0.63(4H,m),1.35-1.50(1H,m), 3.16(3H,s), 3.87(3H,s), 4.12(2H,d,J=7.3 Hz),6.98(2H,d,J=8.8 Hz), 7.74(1H,s), 7.75(2H,d,J=8.8 Hz), 8.09(1H,br). IR(KBr) cm hu −1:3124,1641,1604,1583,1517,1448,1347,1253,1148,1025,864,833. Mass (m/z):349 (M⁺)

Example 127

Preparation of4-carbamoyl-6-(3-chloro-4-fluorophenyl)-2-cinnamyl-2H-pyridazin-3-one

Using6-(3-chloro-4-fluorophenyl)-2-cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-oneas a starting material, the procedures of Example 38 were repeatedlikewise, whereby the title compound was obtained in a yield of 64.8%.

Pale yellow needles (methanol)

Melting point: 211.0-212.0° C. ¹H-NMR (DMSO-d₆) δ: 5.05(2H,d,J=5.9 Hz),6.52(1H,td,J=5.9,15.8 Hz), 6.68(1H,d,J=15.8 Hz), 7.22-7.38(3H,m),7.47(2H,d,J=6.9 Hz), 7.55(1H,t,J=8.9 Hz), 7.95-8.02(1H,m),7.08-8.20(2H,m), 8.59(1H,s), 8.82(1H,brs). IR (KBr) cm⁻¹:3306,3135,1705,1632,1578,1506,1407,1266,959,816,801,735. Mass (m/z): 385(M⁺), 383 (M⁺).

Example 128

Preparation of4,5-dihydro-2-isobutyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one

To a solution of2-isobutyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one (50mg, 0.16 mmol) in N,N-dimethylformamide (10 ml), 10% palladium oncharcoal (45 mg) was added, followed by catalytic reduction at 80° C.Fourteen hours later, the catalyst was filtered off, the solvent wasdistilled off under reduced pressure, and the residue was separated andpurified by silica gel preparative chromatography [developer:hexane/ethyl acetate (1/1)]. Crystallization was then conducted fromchloroform-hexane, whereby the title compound (22 mg, 43.7%) wasobtained as colorless needles.

Melting point: 124.2-125.0° C. ¹H-NMR (CDCl₃) δ: 0.926(3H,d,J=6.8 Hz),0.932(3H,d,J=6.8 Hz), 2.07-2.24(1H,m), 2.82(3H,d,J=4.6 Hz),3.05-3.17(1H,m), 3.33-3.44(2H,m), 3.65-3.70(2H,m), 3.85(3H,s),6.93(2H,d,J=9.0 Hz), 7.36(1H,br), 8.24(2H,d,J=9.0 Hz). IR (KBr) cm⁻¹:3392,3015,1675,1646,1515,1405,1364,1256,1177,1026. Mass (m/z): 317 (M⁺).

Example 129

Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylthiocarbamoyl-2H-pyridazin-3-one

To a solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one(133 mg, 0.40 mmol) in toluene (10 ml), Lawesson's reagent (162 mg, 0.40mmol) was added, followed by stirring at 85° C. for 12 hours underargon. The toluene was distilled off, and the residue was separated andpurified by chromatography on a silica gel column [silica gel: 6 g,hexane/ethyl acetate (4/1 to 2/1)]. Crystallization was conducted fromchloroform-ethyl acetate, whereby the title compound (109 mg, 78.4%) wasobtained as orange needles.

Melting point: 178.0-178.5° C. ¹H-NMR (CDCl₃) δ: 0.47-0.63(4H,m),1.40-1.47(1H,m), 3.39(3H,d,J=4.9 Hz), 3.96(3H,s), 4.20(2H,d,J=7.3 Hz),7.03-7.08(1H,m), 7.61-7.64(1H,m), 7.68-7.72(1H,m), 9.26(1H,s),12.34(1H,br). IR (KBr) cm⁻¹:3111,1641,1548,1521,1506,1425,1289,1267,1117,1015. Mass (m/z): 347 (M⁺).

Example 130

Preparation of2-isobutyl-6-(4-methoxyphenyl)-4-methylthiocarbamoyl-2H-pyridazin-3-one

Using2-isobutyl-6-(4-methoxyphenyl)-4-methyl-carbamoyl-2H-pyridazin-3-one asa starting material, the procedures of Example 129 were repeatedlikewise, whereby the title compound was obtained in a yield of 27.7%.

Orange needles (ethyl acetate-diethyl ether)

Melting point: 116.0-116.6° C. ¹H-NMR (CDCl₃) δ: 1.00(6H,d,J=6.6 Hz),2.36(1H,sept.,J=6.8 Hz), 3.38(3H,d,J=4.9 Hz), 3.87(3H,s),4.17(2H,d,J=7.3 Hz), 7.00(2H,d,J=8.8 Hz), 7.85(2H,d,J=9.0 Hz),9.28(1H,s), 12.40(1H,br). IR (KBr) cm⁻¹:2960,1640,1544,1515,1503,1266,1249. Mass (m/z): 331 (M⁺).

Test 1

(Inhibitory activity against interleukin-1β production)

HL-60 cells were cultured for 4 days until confluence on RPMI 1640medium with 10% fetal bovine serum (FBS) added thereto. The medium wascentrifuged. The supernatant was discarded, and the cells were thensuspended at 1×10⁶ cells/me on RPMI 1640 medium with 3% FBS, andlipopolysaccharide was added to give a final concentration of 10 μg/ml.The culture was inoculated at 1 ml/well to a 24-well plate. A testcompound was added at 1 μl/well, followed by culturing for 3 days. Threedays later, the amount of interleukin-1β in each IC₅₀ value wasdetermined by a comparison in yield with a control to which no testsample was added. Results on some representative compounds are shown inTable 1.

TABLE 1 Inhibitory Activity against Interleukin-1β (IL-1β) ProductionTest compound IL-1β (Example No.) IC₅₀ (μM)  43 0.357  61 0.038  63 0.31 66 0.11  87 0.05 111 0.53 112 0.387 128 0.40 Comp. Comp'd 1 29 Comp.Comp'd 2 46 Comp. Comp'd 3 >100 Comp. Comp'd 4 31.6 (Comp. Comp'd 1)

(Comp. Comd'd 2)

(Comp. Comd'd 3)

(Comp. Comd'd 4)

As is apparent from Table 1, the compounds according to the presentinvention have been found to have extremely good IL-1β inhibitoryactivity compared with the comparative compounds, which are thecompounds disclosed in EOR. J. MED. CHEM., 14, 53-60, 1979 and are knownto have anti-inflammatory and analgesic action.

Capability of Exploitation in Industry

The pyridazine derivatives (1) and their salts, which pertain to thepresent invention, have excellent inhibitory activity againstinterleukin-1β production, and are useful as medicines such aspreventives and therapeutics for immune system diseases, inflammatorydiseases and ischemic diseases.

What is claimed is:
 1. A pyridazine derivative represented by thefollowing formula (1):

wherein R¹ represents a lower alkoxyl group, or a lower alkylthio group;R² represents a hydrogen atom, a lower alkoxyl group, a lower alkylthiogroup or a halogen atom; R³ represents a linear or branched lower alkylor lower alkenyl group, wherein said alkyl or alkenyl group may have oneor more substituents each independently selected from the groupconsisting of a hydroxyl group, a halogen atom, a cyano group, a lowercycloalkyl group, a phenyl group which may be substituted, a naphthylgroup which may be substituted, a pyridyl group which may besubstituted, wherein said phenyl, naphthyl or pyridyl groups whensubstituted have 1 to 3 substituents independently selected from thegroup consisting of a halogen atom, a nitro group, an amino group, and acarbonylamino group substituted with a phenyl, naphthyl or pyridylgroup; and a carbamoyl group that may be substituted with one or moresubstituents independently selected from the group consisting of a loweralkyl group, a lower alkyl group substituted by one or more hydroxygroups, a lower alkyl group substituted with phenyl, naphthyl orpyridyl, and a phenyl, naphthyl or pyridyl group which may besubstituted with one or more lower alkythio groups; R⁴ represents acarboxyl group, a lower alkoxycarbonyl group, a carbamoyl group whichmay have one or more substituents each independently selected from alower alkyl group, a phenyl, naphthyl or pyridyl group, or by a loweralkyl group substituted by one or more phenyl, naphthyl or pyridylgroups, a thiocarbamoyl group which may have one or more substituentseach independently selected from a lower alkyl group, a phenyl, naphthylor pyridyl group, or by a lower alkyl group substituted by one or morephenyl, naphthyl or pyridyl groups, a amino group which may have one ormore substituents independently selected from a lower alkoxycarbonylgroup which may be substituted by phenyl, naphthyl or pyridyl, a C₁-C₅acyl group, a lower alkyl group which may be optionally substituted byphenyl, naphthyl or pyridyl, a lower alkylsulfonlyl group, or a ureidogroup, which may be substituted by one or more lower alkyl groups;wherein the dashed line in formula I indicates that the carbon-carbonbond between the 4-position and the 5-position is a single bond or adouble bond; or a salt thereof.
 2. A pyridazine derivative or a saltthereof according to claim 1, wherein the carbon-carbon bond between the4-position and the 5-position in the formula (1) is a double bond.
 3. Apyridazine derivative or a salt thereof according to claim 1, wherein R¹represents a lower alkoxyl group or a lower alkylthio group; and R²represents a hydrogen atom, halogen atom or a lower alkoxyl group.
 4. Apyridazine derivative or a salt thereof according to claim 1, wherein:R³ represents a linear or branched alkyl group having 1 to 6 carbonatoms or a linear or branched lower alkenyl group having 2 to 9 carbonatoms, wherein said alkyl or alkenyl groups may have one or moresubstituents each independently selected from the group consisting of: ahydroxyl group, a halogen atom, a cyano group, a lower cycloalkyl group;a phenyl or pyridyl group which may have 1 to 3 substituents eachindependently selected from a halogen atom, a nitro group, an aminogroup, a carbonylamino group substituted by one or more phenyl, naphthylor pyridyl groups; and a carbamoyl group which may have one or moresubstituents each independently selected from a lower alkyl group, ahydroxy lower alkyl group, a lower alkyl group substituted by one ormore phenyl, naphthyl or pyridyl groups or a lower alkylthiophenylgroup; and R⁴ represents a carboxyl group; a lower alkoxy-carbonylgroup; a carbamoyl or thiocarbamoyl group which may have one or moresubstituents each independently selected from a lower alkyl group, aphenyl, naphthyl or pyridyl group or a lower alkyl group substituted byone or more phenyl, naphthyl or pyridyl groups; an amino group which mayhave one or more substituents each independently selected from a loweralkoxycarbonyl group, a lower alkoxycarbonyl group substituted by one ormore phenyl, naphthyl or pyridyl groups, a C₁-C₅ acyl group, a loweralkyl group, a lower alkyl group substituted by one or more phenyl,naphthyl or pyridyl groups, a lower alkylsulfonyl group; or a ureidogroup which may have one or more lower alkyl groups as substituents. 5.A pyridazine derivative or a salt thereof that is2-isobutyl-6-(4-methoxy-phenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-cyclo-propylmethyl-6-(4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylcarbamoyl-2H-pyridazin-3-one,2-cyclopropylmethyl-4-ethylcarbamoyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one,or2-(4-chlorocinnamyl)-4-formylamino-6-(4-methoxy-phenyl)-2H-pyridazin-3-one.6. A pyridazine derivative or a salt thereof that is6-(3-chloro-4-fluorophenyl)-2-cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-oneor4-carbamoyl-6-(3-chloro-4-fluorophenyl)-2-cinnamyl-2H-pyridazin-3-one.7. A pharmaceutical composition or medicine comprising a pyridazinederivative or a salt thereof according to claim 1 and a pharmaceuticallyacceptable carrier.
 8. A method for preparing a pharmaceuticalcomposition or a medicine comprising admixing the pyridazine derivativeor a salt thereof according to claim 1 with a pharmaceuticallyacceptable carrier.
 9. A method for inhibiting interleukin-1β productioncomprising administering to a subject an effective amount of apyridazine derivative or a salt thereof according to claim 1, whereinsaid subject has arthritis or rheumatism.